Lithuanian University of Health Science
Faculty of medicine
Kaunas 2020
Department of Genetics and Molecular Medicine
Research of BRCA1, BRCA2, TP53, and CHEK2 mutations and the
risk they raise in the development of breast cancer in young
patients: Literature review
Author: Liat Sariel Maayan
Master’s Thesis
1. TABLE OF CONTENT
2. SUMMARY ...3
3. ACKNOWLEDGMENTS ...4
4. CONFLICT OF INTEREST ...5
5. CLEARANCE ISSUED BY THE ETHICS COMMITTEE ...5
6. ABBREVIATION LIST ...5
7. TERMS ...7
8. INTRODUCTION ...7
9. AIM AND OBJECTIVE OF THE THESIS ...9
10. RESEARCH METHODOLOGY ...9
11. LITERATURE REVIEW -11.1 Results and their discussion ...11
11.2 What is cancer, it's properties, diagnosis, and treatment ...11
11.3 Breast cancer, it's properties, risk factors, diagnosis, and treatment ...12
11.4 Breast cancer in young patients, it's properties, risk factors, diagnosis, and treatment ...13
11.5 Genes related to breast cancer in young patients ………...…...21
12. CONCLUSION ...32 13. PRACTICAL RECOMMENDATIONS ...33 14. REFERENCES ...33
2. SUMMARY
Author: Liat Sariel Maayan
Title: Research of BRCA1, BRCA2, TP53, and CHEK2 mutations and the risk they raise in the
development of breast cancer in young patients
Aim: Review current literature on breast cancer and breast cancer in young patients, risk factors,
treatment strategies, with the focus on the genetic compartment of it.
Objectives:
1. To analyze and assess the risk of development of breast cancer in young carriers of BRCA1 and BRCA2 genes mutations in different populations.
2. To analyze and assess the risk of development of breast cancer in young women carriers of TP53 gene mutations in different populations.
3. To analyze and assess the risk of development of breast cancer in young women carriers of CHEK2 gene mutations in different populations.
Methodology: In this article, we used the information from 48 most relevant systematic reviews and
studies conducted in the last 10 years, written in the English language, published in PubMed, ResearchGate, and Google scholar.
Results: In this study, we summaries the relevant data related to breast cancer, with the focus on breast cancer in young women. We reviewed relevant literature information about breast cancer in young patients. Furthermore, we reviewed the genetic compartment of mutations related to breast cancer in young patients. We reviewed the following genes: BRCA1, BRCA2, TP53, and CHEK2 gene mutations in the relevant subject. The first three gene mutations are considered high risk for the development of breast cancer in young women; the last gene mutation is considered as moderate risk. Each gene mutation has its percentage of appearance in different ethnic groups, and the main related parameter of this literature review is the age of the patients: 35-55 median years of age in most of the articles, if not indicated differently.
High-risk gene mutations have a two-to ten-fold risk of development of breast cancer in young patients with or without a hereditary predisposition. Moderate risk gene mutations had two to four
folds increased risk of developing breast cancer in young patients with or without a hereditary predisposition.
Conclusion:
1. Carriers of BCRA1 and BRCA2 gene mutations are at extremely high risk for the development of breast cancer, an increased risk of about 20-25 percent in lifetime risk for the development of
primary breast cancer, depending on population. Of breast cancer, in young patients, 7% have BRCA1 mutation characteristics with ER-negative and HER2- negative tumors. BRCA2 is associated with high-grade invasive ductal carcinomas, ER-positive, and p53- negative.
2. TP53 gene mutation is high- penetrance mutations; they are mainly HR-positive, HER2-positive tumors. They account for 50% of breast cancer cases regardless of age. The frequency is up to one-third in young patients with breast cancer depends on the population. Furthermore, a mutation in this gene is related to Li-Fraumeni syndrome, which has an increased risk for the development of many human cancers. In Li-Fraumeni syndrome, breast cancer in young patients is about 25-30%.
3. CHEK2 gene mutation is considered a moderate penetrance gene. It presented mainly in younger patients with breast cancer. The most common CHEK2 gene mutation is CHEK2*1100delC, which plays an active role in the development of breast cancer in young women. CHEK2*1100delC
germline mutation increases the risk for the development of breast cancer from two-to five-folds, and its prevalence differs in different populations.
Keywords: breast cancer, young patients, young women, gene mutation, risk factors, BRCA1,
BRCA2, TP53, CHEK2.
3. ACKNOWLEDGMENTS
To my family, for your help and support throughout those years. For standing beside me in my weakest and strongest points of life.
Enormous gratitude is for my husband, Ram. You are my rock and my best friend. I love you and will be forever thankful to have you by my side in this journey called life.
And for you, my daughter to be, for allowing me the ability to work on this thesis. I can't wait to meet you.
4. CONFLICT OF INTEREST
The author reports no conflicts of interest related to this study.
5. CLEARANCE ISSUED BY ETHICS COMMITTEE
No clearance issued by the ethics committee is needed in this study.
6. ABBREVIATION LIST
MRI- Magnetic Resonance Imaging BCSCs- Breast cancer stem cells
BRCA2- Breast cancer-associated gene 2 TP53- Tumor protein 53
CHEK2- Checkpoint kinase 2
HER2- human epidermal growth factor receptor 2 RGFR- Epidermal Growth Factor Receptor FGD3- Facio-Genital Dysplasia 3 gene IBC- inflammatory breast cancer TNBC- triple-negative breast cancer ER- estrogen receptor
PR- progesterone receptor
BCT- conservative breast treatment LRR- Local and Regional Recurrence BCYW- breast cancer in young women
EORTC- European Organization for Research and Treatment of Cancer TEXT- Tamoxifen and Exemestane Trial
SOFT- Suppression of Ovarian Functional Trial HBOC- Hereditary Breast and Ovarian Cancer PV- pathogenic variants
LFS- Li Fraumeni Syndrome
7. TERMS
Carcinogenesis- the initiation of cancer formation.
Luminal A breast cancer- ER-positive and/or PR-positive and HER2-negative and either histological grade 1 or 2 (1,2).
Luminal B breast cancer- ER-positive and/or PR-positive and HER2-positive or ER-positive and/or PR- positive and HER2-negative and histological grade 3 (1,2).
HER2 breast cancer- ER-negative and PR-negative and HER2-positive (1,2).
Triple-negative breast cancer (TNBC)- ER-negative and PR-negative and HER2-negative (1,2).
8. INTRODUCTION
Among women, breast cancer is the second leading cause of cancer-related deaths worldwide,
accounting for approximately 570,000 deaths in 2015, and its incidence and mortality rates are said to increase dramatically in the upcoming years (3,4). It is 100 times more prevalent in women than in men. Breast cancer is a multi-step process involving multiple cell types, and its prevention remains challenging worldwide. Nowadays, the best approach for the prevention of breast cancer is early diagnosis, with a 5- years survival rate of over 80% in developed countries due to early
prevention (3). A widely used screening approach to detect breast cancer is Mammography. And it is treated with combinations of surgery, chemotherapy, and radiotherapy (4).
Breast cancer in young patients is sporadic and uncommon. Less than 25% of patients in
industrialized countries will suffer from it (5–8). The exact definition of young women in breast oncology varies between articles, with the age range of 35-45 is referred to as "young" (4,5).
Its characteristics differ in young women compared to older women. Young women are said to have a higher histological grade and to be classified as estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 positive. Furthermore, it is said that they are more likely to have a local
recurrence, to be diagnosed at advanced stages, and to have lower 5 years survival compared to older breast cancer patients (5). It has a more severe outcome compare to older patients due to multiple reasons (9), including: increased risk for local and systemic recurrence (6), and it is the leading cause of cancer-related deaths compared to older women (4,6,8,10,11).
Mammogram scanning is not used in the diagnosis of breast cancer in young women because it is not sensitive enough due to the high density of breast tissue in young women. Ultrasound is a more sensitive tool in diagnosis (5).
Genes related to breast cancer in young women:
Almost 50 genes have been identified to be related to breast cancer in young women (10). BCYW has a greater genetic predisposition compared to older women. Of women in their 20's 33% have breast cancer attributable to genetic mutation, and in their 30's- 22%. Of these patients, 10-15% will have mutations related to BRCA genes mutation and accounts for 66-75% of all inherited breast cancer cases (6).
BRCA1/2: BRCA1 and BRCA2 are the most famous mutations regarding germline mutations, accounting for up to 40% of familial breast cancer (4,12). They are located on chromosome 17q21 and 13q12, respectively (3,13). BRCA1is a multifunctional protein and have a role in diverse cellular pathways such as DNA damage repair, cell-cycle arrest, apoptosis genetic instability, transcriptional activation, and tumorigenesis. BRCA2 functions as a transcriptional co-regulator. Thus, if they are mutated, they can lead to the development of breast cancer (13).
Of young breast cancer women, 7% had BRCA1 mutation, its characteristics are ER-negative and HER2 – negative tumors (4) and observed as basal-like phenotype. BRCA2- associated breast tumors are predominantly high-grade invasive ductal carcinomas, ER-positive, and p53 negative, and are observed as luminal-like phenotype (13).
TP53: TP53 mutations have a strong association with HR-, HER2+, and basal-like subgroups (1). Point mutations were observed in this gene, accounting for nearly 25% of breast cancer cases
regardless of age (12). One-third of TP53 mutation-positive breast cancer occurs before age 35 years (5).
CHEK2: CHEK2 gene mutation is responsible for breast cancer in younger patients. It has an ER-positive phenotype (12).
9. AIM AND OBJECTIVES
Aim: Review current literature on breast cancer and breast cancer in young patients, risk factors,
treatment strategies, with the focus on the genetic compartment of it.
Objectives:
1. To analyze and assess the risk of development of breast cancer in young carriers of BRCA1 and BRCA2 genes mutations in different populations.
2. To analyze and assess the risk of development of breast cancer in young women carriers of TP53 gene mutations in different populations.
3. To analyze and assess the risk of development of breast cancer in young women carriers of CHEK2 gene mutations in different populations.
10. RESEARCH METHODOLOGY
Search strategy – This literature review was performed by reviewing the current concept of breast cancer in young patients; in most articles, young patients are referred to patients between the ages of 35-55. It was conducted by screening different academic databases such as PubMed, ResearchGate, and Google Scholar. Seventy-six literature sources were reviewed; a total of 48 articles were selected
and are presented in this study. Due to irrelevance to the topic, 6 articles were not included in this literature review, 22 articles were excluded due to more than 10 years after publishment.
The search was restricted to English and the recent 10 years articles, with 2 exceptions- articles 13 and 18.
Selection criteria:
• Articles from the last 10 years. • Breast cancer
• Young patients/ young women • Young patients in the ages of 35-55 • BRCA1
• BRCA2 • TP53 • CHEK2
Exclusion criteria:
• Published date of article- more than 10 years • Not in the English language
• Irrelevant to the topic
• Genes related to breast cancer in women older than 55
76 articles reviewed in this study using key words.
22 articles excluded due to old data (10 years or more after publishing)
54 articles were potentially relevant and were read throughout
6 were excluded due to irrelevance to the topic or not written in English language
Data collection process: In this study, we reviewed 76 articles; of those, 22 were excluded due to old data (more than 10 years), 6 articles were excluded due to irrelevance to the topic. In this study, we used 48 articles. These articles were selected based on their clinical relevance and applicability. All the articles cited and found in the references were reviewed throughout.
11. LITERATURE REVIEW
11.1 Results and their discussion
In this study, we reviewed and summarized the relevant data related to breast cancer, mainly about breast cancer in young women with a focus on its genetic variants of mutations related to it. We reviewed the following genes: BRCA1, BRCA2, TP53, and CHEK2. The first three gene mutations are considered high risk for the development of breast cancer in young women, which means they have two-to ten-fold risk in the development of BCYW with or without hereditary predisposition. The last gene mutation is considered a moderate risk, which means a two-to four-fold increase in BCYW with or without a hereditary predisposition. Each gene mutation has its percentage of appearance in different ethnic groups, and the main related parameter of this literature review is the age of the patients 35-45 median years of age in most of the articles if not indicated differently. We concluded that BCYW differs from BC in older women by its unique biology, the tumor subtypes, and risk factors. Furthermore, BCYW show at a higher stage of development, higher
metastatic rate, and lymph nodes involvement have higher mortality rates compared to older patients.
11.2 What is cancer, its properties, diagnosis, and treatment
Cancer worldwide causes a significant health problem, with increasing incidences annually. It was estimated that there would be 14.1 million new cancer cases and 8.2 million cancer deaths in the year of 2012 (14). Cancer is characterized by uncontrolled cell growth and the acquirement of metastatic properties. It happens when healthy cells convert to cancer progenitor cells that grow and undergo epithelial-mesenchymal transition (15). Cancer cells are complex tissues composed of multiple types of cells that take part in heterotypic interaction with one another (16).
Cancer comprises of six biological capabilities: sustaining proliferative signaling
(chronic proliferation), evading growth suppressors (working as central control that govern the cell’s decisions to proliferate or to activate apoptotic programs), resisting cell death, enabling replicative immortality, including angiogenesis, and activating invasion and metastasis. Underlying these capabilities are genome instability, which generates the genetic diversity, and inflammation which fosters multiple hallmark functions (16).
Metastasis begins with local invasion, then intravasation of cancer cells into nearby blood and lymphatic vessels, movement of these cells in the vessels followed by their escape to the Lumina of such vessels into the parenchyma of distant tissues (also known as extravasation), where they form small nodules of cancer cells (micro-metastases) and finally, the growth of the micro-metastasis into macroscopic lesions (also known as “colonization”) (16).
A variety of different viruses can cause cancer in humans. Sunlight or ultraviolet light can cause skin cancer. Tobacco in cigarette smoking is known to cause lung cancer. Medications began to be
frequently identified as carcinogens (17).
Early detection of cancer and risk assessment of it is the main priority of health care diagnosis (18). Many types of cancer can be resistant to conventional therapy, and different combinations of drugs and therapies are the only way to destroy tumor cells (19). In the past, cancer was classified and treated only according to the organ of origin or simplistic histomorphology features (14). Cancer treatment nowadays is mechanism-based targeted therapies (16). The therapeutic arsenal includes surgery in case of solid tumors, antitumor drugs, radiation, which is the treatment of choice nowadays, and gene therapy. In recent years immunotherapy became an essential therapeutic alternative and is the first choice of treatment in many cases. The newest technology in cancer treatment is nanotechnology, which offers controlled drug delivery, combining imaging and treatment, applying hyperthermia, and provides direct target therapy (19).
11.3 Breast cancer, its properties, risk factors, diagnosis, and treatment
Among women, BC is the most common neoplasia, representing 25.2% of total cancer cases (20). It is the second leading cause of cancer-related deaths worldwide, accounting for approximately 570,000 deaths in 2015, and its incidence and mortality rates are said to increase dramatically in the
upcoming years (3,4,20,21). Besides, it is 100 times more prevalent in women than in men. More than 1.5 million women around the world are diagnosed with breast cancer every year (3).
Risk factors for developing breast cancer are age (incidence increase with age (5)), sex
(females>males), family history (for example, Familial Breast Cancer Syndrome (5)), estrogen, gene mutations, and unhealthy lifestyle (3). Another risk factor is delayed childbirth when delivering the first child after the age of 30 years, or chest radiation for Hodgkin's lymphoma (5).
Nowadays, the best approach for the prevention of breast cancer is early diagnosis, with 5-years survival rates over 80% in developed countries due to early prevention (3). In the metastatic stage of breast cancer, the median survival time is less than 24 months (4). A widely used screening approach to detect breast cancer is Mammography. Other screening options for prevention include MRI, chemoprevention, and biological prevention (3).
Breast cancer is metastatic cancer, which is commonly transferred to distant organs such as the liver, bones, lungs, and brain (3). It is now established knowledge that women with breast cancer are treated with combinations of surgery, chemotherapy, and radiotherapy (4).
There are two hypothetical theories for breast cancer initiation and progression: 1. The cancer stem cell theory- which suggests that all tumor subtypes are derived from the same stem cell or progenitor cells, which will lead to different tumor phenotypes.
Stochastic theory- each tumor subtype is initiated from a single cell type (stem cell, progenitor cell, or differentiated cell), and random mutations can gradually accumulate in the breast cells leading to their transformation into tumor cells (3).
10.4 Breast cancer in young patients its properties, risk factors, diagnosis, and treatment
BCYW is very rare and uncommon; less than 25% of the patient population in industrialized countries will suffer from it (5–8,21). Thousands of new cases of BCYW are diagnosed worldwide every year, with the highest rates in Italy, France, and the United Kingdom, the lowest incidence in less developed countries (11,22).
The exact definition of a young woman in breast oncology varies between articles; with an age range of 35-45 is referred to as young (4,5,20). The chances of developing breast cancer in the next 10
years in women aged 30 are 0.44% or 1 in 288 (7). Approximately 7% of all women diagnosed with breast cancer in the years 2000-2005 were below the age of 40 (6).
Each year, in the US, over 24,000 young women, aged 40 or younger, are diagnosed with breast cancer, and 2,500 dies because of it (6,22–24). Furthermore, every year, in the US, around 10,000 women aged 40 or less are diagnosed with invasive type of breast cancer (4,22,24). It is a leading cause of cancer-related deaths in this age group compared to the older-aged group (9,11,22). For example, in Saudi Arabia, breast cancer is a major cause of morbidity and mortality among young females. 45 % of all female breast cancer patients develop it before the age of 45 years of age compared to 9.6% in the USA (1).
It is unclear if the higher risk of death is due to the age itself or whether it is driven primarily by the tumor's subtype, for example, Luminal A-subtype tumors and human epidermal grow factor receptor 2 overexpression subtype tumors (6,10).
In a study conducted between the years 2000-2008, it was found that the median age at diagnosis of BCYW was 36 years. Moreover, most women had ductal histology (86.5%) and grade Ⅲ disease (58.9%). Approximately 50% of women had node-positive disease, 27% had multifocal tumors. were ER-negative, were HER2 – positive tumors. This study reported high rates of lymphovascular invasion and lymphocytic infiltration. In a different study conducted by Gnerlich et al., it was found that young women at the age of diagnosis were more frequently diagnosed with large tumors, lymph node involvement, poorly differentiated tumors, and ER-negative tumors- those findings showed the aggressive nature of breast cancer in young women. In a study conducted by the California Cancer Registry was reported that there was a statistically significant HER2- higher expression in younger women (4).
Breast cancer incidence differs according to race. In the West, 4% of the diagnosis of breast cancer is made in women aged 35. In the East, 13% of the breast cancer diagnosis is made in women aged 40 and 5% in women aged 35 (4). It is more common in Caucasian women than in African Americans. But, in young women, breast cancer is twice as common in African American women. They are more likely to have hormone receptor-negative tumors compared to Caucasians, furthermore, they are more likely to be diagnosed with a more advanced stage (5).
The worst prognosis for breast cancer in young patients appeared only in low- and medium-risk subgroups rather than in high-risk subgroups (10).
Some risk factors for BCYW include early childbearing- accumulative evidence suggests that pregnancy and breastfeeding seem to be a risk factor in the short term. It can be explained by the increased risk of developing breast cancer 2-7 years following pregnancy (5,12). A family history of breast and/or ovarian cancer increase the risk of two to four-folds for the development of breast cancer (5,25). Furthermore, they have an increased risk of collateral breast cancer in young patients (26). Ashkenazi Jewish ancestry is another risk factor (5). Western populations and black women are another risk factor- mainly due to late screening and diagnosis and an average age of the younger population (12,25).
The characteristics of BCYW differ from BC in older women (5,20–22). BCYW have worse outcome compare to older patients due to multiple reasons, including delays in diagnosis,
unfavorable clinicopathologic features, and have more aggressive subtypes (5,9,22). Therefore, they tend to present at a more advanced stage, higher grade, hormone receptor-positive, triple-negative, HER2/ neu-positive, have a lymphovascular invasion, be triple receptor-negative, and basal-like carcinomas (2,4–8,20–22,27,28). Furthermore, they have higher proliferation rates and are poorly differentiated (20). It's inferior outcomes include increased risk for recurrence, local and systemic (5,6,20,25), they are diagnosed at an advanced stage, have lower 5 years survival (5,25), and it is the leading cause cancer-related deaths compared to older women (4,6,8,10,11); thus it requires more aggressive treatment- radical surgery, higher dose of radiation, more aggressive chemotherapy, and prolong hormonal therapy (28). Young African American women, compared to young white women, had an increased risk of developing breast cancer of higher grade, and estrogen receptor-negative cancers. In a study conducted by the Carolina Breast Cancer Study, it was found that 39% of young African- American women had basal-like breast cancer compared to 16% of non-African American women. Of the 36% had luminal A cancers compared to 54% of non-African American young women (9).
In recent years there has been accumulative evidence that claims that the differences in breast stroma in young patients and the changes occurs in pregnancy and breastfeeding can contribute to the
difference in the biology of the tumors of older patients with breast cancer. Furthermore, tumors arising during or shortly after pregnancy have unique biological features. In recent years two studies
were published suggested worse outcomes in breast cancer with luminal- B tumors in young patients compared to older women (12).
There are four types of breast cancer which are clinically relevant for young patients: luminal A (ER+, PR+, HER2-, Ki67 low), luminal B (ER+, HER2-, PR-, or Ki67 high), triple-negative breast cancer (ER-, PR-, and HER2-), and HER2 over-expressing tumors (HER2+) (12,25), of which TNBC and HER2 overexpression are the most aggressive forms of breast cancer and are over-represented in BCYW (25,29).
In the overall population, including all age groups, TNBC is represented by 12%; in BCYW, it is 26%. BCYW is more likely to present with triple-negative, TP-53 positive, and HER2
overexpression than among older women (25). Little is known about TNBC's etiological factors that promote its initiation and development (29).
In a study conducted in the UK which included 2,956 women, found that the median age at diagnosis was 36, the majority of patients had ductal histology (86.5%), grade Ⅲ tumors (58.9%),
node-positive disease (50.2%), and multifocality (27%) were seen. Moreover, one-third of the tumors in young patients were ER-negative, and one quarter was HER2- positive. In a different study
evaluating 399 young patients conducted by Young Women's Breast Cancer Study, demonstrated high rates of lymphovascular invasion (34%) and lymphocytic infiltration (24%). In the most extensive study conducted till this day, by Gnerlich and colleagues, including more than 200,000 young patients younger than 40 years of age, was found that they were commonly diagnosed with larger tumors (P< 0.0001), nodal involvement (P< 0.0001), poorly differentiated tumors (P< 0.0001), and endocrine receptor-negative tumors (P< 0.0001) (12).
A study conducted by Azim and colleagues, including 3,522 young patients, found that they had a significantly higher incidence of basal-like tumors (34.3%) compared to the older population. Furthermore, it was found that they had a higher proportion of HER2 positive tumors. In contrast, BCYW were less likely to have luminal-A breast cancers compared to other groups of age. Other studies also found a lower prevalence of ER-positive, HER2- negative tumors in young patients, but a high proportion of triple-negative tumors, and HER2 expression irrespective of ER status (12). In a different study, including 399 women younger than 40 years old, 33% had liminal A tumors, 35% had luminal B, 11% had HER2, and 21% had triple-negative. BCYW had luminal B tumors and a lesser proportion of luminal A tumors compared to the general population of BC. Furthermore, most of them had hormone receptor-positive disease. Overall, 66% were ER-positive, and 31% were HER2-positive. A majority of them had histological grade 3 BC (30 years = 64%, 31–35 years = 57%, and 36–40 years = 53%). A study conducted by Bacchi et al. reported a high prevalence of
luminal B tumors in BCYW. In their study, BCYW tumors had low expression of ER, overexpression of HER2 in 33.6% of young women (2).
Breast cancer subtypes according to age, Picture taken from (12)
The finding in Azim and colleagues' study suggest that the younger the patient is, the more aggressive tumor features it will have. Yet, it appears as if the differences are more subtle in very young breast cancer patients between the ages of 35-40. Furthermore, young patients had more basal-like tumors, but after adjustments for the subtypes, no distinct molecular aberrations were found to be related to age (12).
In a more recent study conducted by Azim and colleagues, they analyzed a pooled gene expression dataset, including 1,188 and 2,334 breast cancer patients of various ages. They aimed to evaluate the association between patient's age and almost 50 identified genes that are related to early-onset breast cancer. It was adjusted for the differences in the molecular subtypes of breast cancer, its histological grade, tumor size, and nodal status. The results of the first dataset (n = 1,188, ≤40 years = 191) showed that, independent of subtype, grade, and stage, YBCW have higher expression of RANK- ligand (P< 0.0001), c-kit (P < 0.001), in addition to mammary stem cell (P < 0.0001) and luminal progenitors and BRCA1 mutation signatures (P= 0.007). moreover, there was more disruption of the mitogen-activated protein kinase and PI3K pathways (P < 0.0001) and lower expression of BRCA1 (P= 0.003) and several apoptosis-related genes, for example, FAS (P= 0.03) (12).
Breast cancer subtypes according to age determined by immunohistochemistry, Picture taken from (12) The diagnosis of breast cancer in young patients should proceed along with standard algorithms for the evaluation of breast cancer in any age, including clinical examination, imaging, and histologic confirmation (4).
Mammogram scanning is used in the diagnosis of breast cancer in older women. Still, in young patients, they are not sensitive enough to diagnose breast cancer due to the high density of breast tissue in young women. That is why they are not shown to be clinically beneficial or cost-effective in the diagnosis (5). Ultrasound is often used as a more sensitive tool in the diagnosis of BCYW, and it can distinguish solid masses from simple or complex cysts (5,8). MRI is often used to determine the extent of disease. If a genetic predisposition is suspected, an MRI of the breast should be performed (8).
BCYW management strategies, recommendations, and treatment options should not be based on age only, instead, it should be based on its biological features of the type of cancer (4,6,11). Besides treatment, there should be psychosocial considerations that should be addressed as part of a comprehensive, multidisciplinary team approach, including fertility discussions and preservation,
sexual dysfunction, behavioral health, and quality of life. When breast cancer occurs in very young women, it can have a lot of negative impacts on her everyday life. She has no peers with the disease to talk to; she might not complete her education; she might not be in a long-term relationship, with or without children, etc. If she is without children, treatment might disrupt her childbearing plans; if she has children, she might fear her ability to raise them or leave them prematurely. Treatment in her 40's may precipitate early menopause. Furthermore, cancer treatment adds stress to everyday life issues and career challenges (7,23,24,27). A systematic review covering 28 studies of survivors of women younger than 50 years of age found that anxiety, depression, and impaired quality of life are common among them, as well as concerns about weight gain, premature menopause, menopausal symptoms, and infertility (23).
Treatment depends on factors such as tumor size, location, ability to achieve an excellent cosmetic outcome, prior radiation or contraindication for radiation, and of course, patient preference (5). Systemic chemotherapy is the golden standard approach for most cancer types, although the
scientific community has been attracted to targeted therapy over the past decade for the treatment of breast cancer (4). Another issue arising from chemotherapy treatment is the fact that it causes an increased risk for infertility in BCYW; in a study done in this subject, it was found that all of the patients receiving chemotherapy, low levels of the ovarian reserve were detected. Furthermore, in some of the patients' premature ovarian insufficiency was detected (30). Recent data from several studies showed that the optimal endocrine therapy should be an extended duration of tamoxifen (11). Despite an increased risk for local recurrence rates at a young age, there is no contraindication to do breast conservation therapy followed by radiotherapy or mastectomy because both treatment plans have the same long-term survival (5,8,11). That is said, many BCYW chooses bilateral mastectomy in recent years (8,11). If a woman chooses to go through bilateral mastectomy, an immediate reconstruction, including skin and nipple-sparing techniques, should be offered (6). In BCYW, mastectomy is preferred over breast conservation for improvement of local and regional recurrence (27). Long term results of the EORTC showed that younger age and BCT were risk factors for LRR, with 2.8 times higher risk compared with older women. In all ages, patients that were treated with BCT had a 1.8 times higher risk for LRR compared with patients treated with total mastectomy (6). Neoadjuvant endocrine therapy should not be proposed to young women outside clinical trials due to limited evidence available. Data on HER-2 influence on adjuvant endocrine treatment is limited.
Still, in the presence of oophorectomy, the impact of endocrine treatment with adjuvant tamoxifen on breast treatment outcome is comparable in patients with HER-2 positive and HER-2 negative tumors (8). It is also suggested that HER-2 positive breast cancer have similar outcome when comparing to other prognostic factors and derive similar benefit from adjuvant treatment with trastuzumab as older women with breast cancer (9).
In the case of inflammatory breast cancer, where it is not appeared to be linked to genetic
background, its management should be the same as in the treatment of breast cancer in older women. In the HERA trial, it was demonstrated that women of all age groups had similar benefits from adjuvant therapy with trastuzumab (8).
Advanced breast cancer in young women is defined as metastatic disease diagnosed in women younger than 40 years of age. In recent years, in the US, its incidence increased from 4.4% to 7.2%, and its 5-years survival rate is only 31% compared to 87% in loco-regional breast cancer in young women. There are only a few proven treatment strategies for advanced breast cancer, but even fewer for advanced breast cancer in young women. Whenever possible, the metastatic lesion should be biopsied and tested for confirmation of diagnosis, histology, and biology, mainly if late relapse had occurred (8).
BCYW are at higher risk for developing long term and late effect of the cancer treatment, for example- fractures from early osteoporosis, cardiac failure, and second cancers can occur (7).
11.5 Genes related to breast cancer in young patients
Several research studies found that BCYW exhibit higher genetic susceptibility and specific genomic signature in comparison to older women with BC (20).33% of women in their 20's and 22% of women in their 30's have breast cancer that is attributable to genetic mutation (6).
Gene mutations are categorized according to their relative risk they add; they grouped into highly penetrant mutations which are associated with a risk for the development of BC greater than 5, intermediate-penetrant mutations confer relative cancer risk from 1.5 to 5. Low-penetrance loci have a relative risk of approximately 1.5. Highly penetrant gene mutations are associated with hereditary cancer syndromes, and more than 200 genetic syndromes are linked to it. For hereditary BC
For example, high incidence of cancer within the family, the occurrence of the same type of cancer within the family, early onset-age of presentation (< 50 years), bilaterally, and multifocality (20). The main goal of this study is to review some of the significant genes related to breast cancer in young women:
BRCA1 and BRCA2 are two famous anti-oncogenes for breast cancer risk. They are located on chromosome 17q21 and 13q12, respectively (3,13). They both encode tumor suppressor proteins (13), and function in DNA damage response in the cell (31). BRCA1 and BRCA2 are the most common mutations regarding germline mutations, accounting for up to 40%-70% of familial breast cancer (4,6,7,12,13,20,31–34), especially triple-negative phenotype (8), and are attributed to the HBOC (20). The majority of these mutations are small insertions and deletions or point mutations (31). If an individual inherits deletion mutation in either BRCA1 or BRCA2 genes, the risk for developing breast cancer increase significantly, around 45-80% increase risk (13,20). Furthermore, in comparison to nonhereditary breast cancer, 80% of BRCA1 mutation carriers will be diagnosed with BC before menopause. BRCA1 and BRCA2 are inherited as an autosomal dominant manner (13). In total, about 20-25% of hereditary breast cancers and 5-10% of all breast cancers are caused by BRCA1/2 mutations (13,35). While analyzing BRCA1 and BRCA2 sequence variants, there was found 16 different sequence variants- seven in BRCA1 and nine in BRCA2 (31).
BRCA1is a multifunctional protein known to interact with different proteins to have an essential role in diverse cellular pathways such as DNA damage repair, cell-cycle arrest, apoptosis genetic
instability, transcriptional activation, and tumorigenesis (13,20).There are more than 500 missense variants of unknown significance that have been linked to BRCA1. The lifetime risks of BC are as high as 80% among women carrying BRCA1 mutations, with a higher frequency of cancer risk at younger ages (20). Mutations in BRCA1 are mostly observed in three domains called: N-terminal RING domain encoded by exons 2-7, coding regions of exons 11-13 ("serine cluster"), and BRCA1 C- terminus encoded by exons 16-24 or BRCT domain. Exons 11-13 contains a large amount of clinically relevant mutations and is highly crucial in tumor suppressor function of BRCA1 (13). High-grade triple-negative BC or basal-like tumors are more common in women with BRCA1 mutations (5,13,36). The high expression of BRCA1 mutation rate and the luminal progenitors and the c-kit in young patients may explain why young women develop more frequently basal-like
tumors (4,12,13) and lack expression of estrogen receptor (ER) (13). The chances for developing ER-negative high-grade tumors in BCYW aged 30-34 years with a BRCA1 mutation is almost 30% (20).
BRCA2 functions as a transcriptional co-regulator (13), and it encodes a protein that repairs double stranded breaks during homologous recombination. The majority of these mutations are frameshift with a small number of missense mutations (20). It is associated with breast cancers, which are more likely to be high-grade invasive ductal carcinomas, but with a luminal phenotype- ER and PR
positive, p53 negative, and HER2 negative (5,13,20,36). BRCA2 contains 27 exons with eight internally repeated sequences called the BRC motif. It's composed of C- terminal domain that implicated to have DNA binding property (13). Pathologic and immunohistochemical features of tumors associated with BRCA2 are similar to sporadic cases (5). There are some similarities between the exons of BRCA1 and BRCA2, but there are no significant sequences of homology between them (13,20). In Finland, monogenic trait mutations account for 5-10% of all BC cases. BRCA1 and BRCA2 are responsible for 20% of hereditary BC. Moreover, BRCA2 mutations are more common in the Finnish population than BRCA1 mutations (31). In the Chinese population, BC is usually
diagnosed at a relatively young age. However, the prevalence of BRCA1 and BRCA2 germline mutations are much lower or absent in this population (33). Thus, if these genes are mutated, their dysfunction can lead to the accumulation of genetic alterations and can lead to the development of cancer (13).
In a population-based case-control, the chances for women to have breast cancer under the age of 35 with detectable BRCA1/2 mutation was 9.4% (compared to the general population- 0.2%) (5,20). In this study, they found that 12% of women aged ≤45 years with a family history of BC had germline mutations in BRCA1 or BRCA2 (20).
An important finding, found in an analysis study, was that 7% of young breast cancer women had the BRCA1 mutation, BRCA1 carriers are significantly younger, had more ER-negative, and HER2 – negative tumors (4).
A French study has found that the prevalence of BRCA1 mutations in women under 35 years that had triple-negative poorly differentiate tumors to be 28.6% (4 out of 14) regardless of their family
age with ER-negative, grade 3 tumor has 26.5% of harboring BRCA1 mutation (compared to 5% in women in the same age but with any tumor type) (5).
In a large-scale analysis conducted with 3,345 young patients younger than 50 at the time of diagnosis, 7% of them had BRCA1 mutation. However, the carriers of this type of mutation were significantly younger compared to older patients, 41.9 years compared to 44.1 years of age, respectively. Moreover, they had more ER-negative and HER2 -harmful types of tumors (12). Women with favorable BRCA1/2 mutations have a 40-50% chance for developing second primary breast cancer. A second study found no detectable mutations of BRCA1/2 negative women in 95 women diagnosed with breast cancer under the age of 30 (5).
In a recent meta-analysis studying contralateral BC in BRCA1 and BRCA2 mutation carriers, it showed a cumulative risk of 5-years survival was 15% and 9%, respectively. In 10-years survival, it increased to 27% and 19%, respectively (6).
A study conducted by Kuchenbaecker et al., it was reported a rapid increase in primary BCYW in the case of BRCA1 mutation carriers aged 30-40 years of age. Moreover, they reported an increased risk for the development of BC in the case of BRCA1 or BRCA2 mutation carriers with a first and second-degree family history of BC (26).
In a different study conducted in Mexico, they estimated the frequencies of BRCA1 and BRCA2 mutations among 190 women with TNBC, without a family history, and age of diagnosis was less than 50 years of age. These patients were screened for 115 recurrent BRCA mutations, including a significant common mutation related to the Mexican population BRCA1 ex9-12del. This mutation was detected in 44 patients with TNBC (23%). In this study, they detected 43 patients with mutations in BRCA1 and one mutation in BRCA2. Out of the 44 women with mutations, twenty (45%) had first-or second-degree relatives with BC. The BRCA1 943INS10 mutation was detected in five patients. This mutation is commonly reported in the African population. The BRCA1 R71G mutation was seen in four patients. This mutation is common in the Spanish population. The BRCA1 2925del4 mutation was seen four times, it is most common among the Jewish population, but none of the patients in this study reported been from Jewish ancestry. The BRCA1185delAG mutation was seen in three cases. It is common among high-risk BC patients of Mexican descent in the US. The BRCA1
R443X mutation was seen four times, mainly in women from Western European origin. The BRCA1 3878delTA mutation was reported twice, and it has been identified in Latin American women. The BRCA1 Q1200X and A1708E mutations were seen once each. The Q1200X mutation is prevalent among Western Europeans. The A1708E mutation is common to Spanish and Colombian
populations. The prevalence of mutations among women diagnosed before the age of 40 years was 30.3%, and above the age of 40 years was 18.3%. Seven recurrent mutations were found in 39 patients (this accounted for 89% of the total mutations) (37).
In a study analyzing the pathogenic variants (which are associated with the risk of hereditary BC) in genetically different cancers, it was found that PVs were found in 9.3% of women, from whom the prevalence of BRCA1 PVs was significantly higher among women with TNBC younger than 40 years of age. PVs in BRCA2 were similar in prevalence to other BC subtypes with TNBC. PVs in BRCA1 and BRCA2 were identified in half of the patients tested, are associated with the lifetime risk for development of BC 41-90% (38).
In a case-control study conducted by Dennis and colleagues, they analyzed the relation between BRCA1 pathogenic germline gene mutation and alcohol consumption. In their study, they found that higher alcohol consumption or no alcohol consumption can reduce the risk for BC (p-trend=0.03, n=1480). In contrast to their study, in a different case-control study performed by Lecarpentier and colleagues, McGuire and colleagues, and a prospective cohort study by Cybulski and colleagues observed no significant association between alcohol intake and BC risk among BCYW with BRCA1 gene mutation. In a case-control study conducted by Gronwald and colleagues, no association was observed between coffee consumption and BC risk among 348 women with BRCA1 pathogenic germline gene mutations. In a study conducted by Nkondjock and colleagues, they assessed the daily caloric intake. They found that a daily energy intake of more than 2339 kcal/day was associated with triple the risk for developing BC.
In contrast, in the study by Moorman and colleagues, they found no effects between BMI one year before the diagnosis of at age 18 and BC risk. In a retrospective cohort conducted by Manders and colleagues, they assessed 218 women with BRCA1 and BRCA2 pathogenic gene mutations. They found that the risk for developing BC was doubled when the current weight was ≥72kg. Kim and colleagues assessed the intake of folic acid, B6, and B12 vitamin supplementation. They found that
daily use of prenatal supplements was associated with reduced risk of developing BC for 400 women with BRCA1 and BRCA2 pathogenic gene mutations (32).
Deleterious mutations in BRCA1 and BRCA2 genes are infrequent but were associated with increased risk for the development of BC. A substantial risk factor for the development of CBC in the absence of BRCA1 or BRCA2 mutations is a family history (26,39). Among the non-carriers of the BRCA1 or BRCA2 mutations, the history of the first-degree relative vs. no family history had nearly two-fold increase risk for CBC. An additional risk was associated with a family history of relatives diagnosed at a young age and relatives with bilateral disease. Their risk was three-folds higher and ten-folds higher, respectively. Furthermore, mutations in BRCA1 and BRCA2 shown an association with increased risk for the development of second primary BC (26).
As a treatment plan, BRCA mutation should not promote recommendations for contra or ipsilateral mastectomy. It can be used for risk reduction only (5). Besides, breast conservation treatment should be considered (7). Poly ADP ribose polymerase inhibitors are showing promising treatment
management for BCYW with BRCA1 or BRCA2 mutations (12).
In conclusion, BRCA1 and BRCA2 mutation carriers' women are at extremely high risk (more than 20-25% increase in lifetime risk) for the development of primary BC. Thus, it is recommended to start with annual surveillance with Mammography and MRI with or without the US as a risk
reduction measurement (8). If cancer develops in women under the age of 35-45, she should consider familial breast cancer syndromes and perform genetic testing for BRCA1, BRCA2, and TP53
mutations (5,8,20). Women with the genetic predisposition of deleterious mutations in BRCA1 or BRCA2, diagnosis is made for the detection of early disease. It should include clinical exams every 6-12 months starting at the age of 25, yearly MRI screening at age 25 until age 30, then annual Mammography and MRI after that (6).
Relative frequency of mutations in breast cancer genes according to age, Picture taken from (20)
TP53 gene is located on chromosome 17p13.1 (40), encodes a peptide that is responsible for cellular stress response and regulates the expression of target genes, including cell cycle arrest, apoptosis, senescence, DNA repair, and change in cell metabolism (20,40–42). This gene contains 11 exons and comprises four distinct types of functional domains: two transactivation domains, a centralized DNA binding and mutation hotspot domain, an oligomerization domain, and a regulatory domain. TP53 mutations are mostly located and clustered within the DNA-binding domain (40). TP53 mutations are the most common in the protein variants among cancer cells. Of these somatic and germline alterations, 80% are missense mutations. These mutations lead to the synthesis of stable protein mutation and its accumulation in the nucleus of the tumor cells (41). Mutations in TP53, which result in BC, are related to poor survival independent of other risk factors (1,7,40), increased resistance to chemotherapy and radiation, with increased relapse rates (40).
Furthermore, it has a strong association with HR+, HER2+, and basal-like subgroups (1,38,42). The lifetime risk of development of BC in women with TP53 germline mutations is 50%. In BCYW, the frequency was reported to be from 1-7% and can be as high as 30% if diagnosed before the age of 30 years (20). Point mutations were observed in this gene, accounting for nearly 25% of breast cancer cases regardless of age (12).
Mutations in TP53 are also related to Li-Fraumeni syndrome; it is an autosomal-dominant cancer syndrome caused by TP53 heterozygous germline mutations (36,40,43). This syndrome is associated with an increased risk for the development of many human cancers (for example, breast, sarcoma, brain, and adrenocortical cancers). However, early-onset of BC is the most common type of tumor in women with TP53 germline mutations (20,36,38,40,42,43), accounting for about 25-30% of LFS associated cancers (40). Most of the mutations in this syndrome are single-base substitutions. They are diverse in their type, sequence context, their position, and their structural impact, making it very hard to identify the mutation patterns with the cancer type and its etiology (43). LFS patients carry a lifetime risk of 50% for the development of BC by the age of 60 years, with significant risk before the age of 40 years (36). Almost 70% of patients with this syndrome carry heterozygous germline mutations that result in the expression of wild-type and mutant type of TP53 in their normal cells (41). This syndrome can explain 1% of all BC cases, however, it accounts for 5% of cases of BCYW younger than 30 years of age (20).
One-third of TP53 mutation-positive breast cancer occurs before age 35 years. In the study of Gonzalez and colleagues, they examined 525 patients whose samples were submitted for clinical TP53 genetic testing, 91 patients (17%) had detectable mutations. In patients under 30 years with no family history of first or second-degree relatives, 1 of 14 (7%) had a detectable mutation (5).
In a study conducted by Stephens and colleagues, evaluating genes related to breast cancer in pregnant and non-pregnant young patients, no differences were found. It should be noted that in this study, they studied only 12% of known TP53 genes, and found only 5% of patients to have
mutations related to TP53 genes (12).
In a review, it was found that the frequency of TP53 mutations in BCYW was 10.74% compared to 2.4% in older patients. Furthermore, it was reported that the frequency of the TP53 mutation is comparable to the BRCA2 mutations in young women diagnosed with BC before the age of 35 years (20).
Three studies have found that the majority of BC related to TP53 mutations were HER2 positive phenotype. Melhem-Bertrandt et al. found in their study that the numbers of HER2 positive tumors among TP53 was significantly higher than among non-carriers (40).
Recently, McCuaig et al. suggested that TP53 mutation is more prevalent than BRCA1 or BRCA2 mutations in BCYW without a contributory family history. Therefore, they are recommending genetic testing for BRCA1, BRCA2, and TP53 in these patients (40).
If cancer develops in women under the age of 35-45, she should consider familial breast cancer syndromes and perform genetic testing for BRCA1, BRCA2, and TP53 mutations (5,8,20,42). Besides, HER2 amplification can be a useful marker for the identification of TP53 germline mutation because this amplification was seen in six out of seven BC tumors in TP53 mutation carriers (86%) (42). Furthermore, like preventative care, mastectomy for risk reduction should be offered to women with LFS to reduce the risk for primary BC (40).
In conclusion, TP53 mutations are high-penetrance mutations that also have the potential for
prognostic, in particular, hormone receptor-positive tumors, and predictive markers, as well as acting as targets for pharmacological intervention in BC (43).
Relative distribution of mutations in BCYW, Picture taken from (21)
CHEK2 gene consists of 14 exons, and it is located on the long (q) arm of chromosome 22. It composed of three domains: the N-terminal SQ/TQ cluster domain, forkhead associated (FHA)
domain, and a serine/threonine domain (33,44,45). CHEK2 gene mutation is considered a moderate penetrance gene (20,31,44). It is a gene that encodes G2 checkpoint serine-threonine kinase 2 that is responsible for DNA damage response (20,21,26,44,46), and replication blocks, preventing mitosis (20). It is a rare germline mutation related more commonly to BCYW (12,26,33,38,45). Furthermore, it is associated with increased risk for the development of second primary BC (26). To date, less than 100 mutations were identified in CHEK2 gene- 55 missense/nonsense mutations, 2 gross
deletions, 11 small deletions, 1 small insertion, 3 splice-site mutations, and 2 mutations in regulatory regions (45).
CHEK2 frameshift and missense mutations (c.1100delC, c.IVS2 +1G>A, del5395, p.I157T) are predominantly ER-positive (46). CHEK2*1100delC mutation is an important BC predisposing variant, with increased risk for the development of BC (44). CHEK2 p.I157T missense mutation has been reported with lobular carcinoma (46). These two mutations were widely studied in many populations, and their prevalence differs greatly among different populations. They occur mainly in the European population with a 2-fold increased risk for BC. However, these variants were not identified in Asian, South Americans, and Spaniard's populations (33). In a recent study conducted in Denmark evaluating 25,571 patients, it was found that 1.8% of patients were CHEK2 heterozygous. These patients were younger, were more likely to present with premenopausal, and to have ER-positive diseases (12). In the Chinese population, CHKE2 germline mutations are much lower or even absent, in comparison to the Caucasians (33).
In a study reported by Kuchenbaecker et al., was mention that mutation in CHEK2 was associated with increased risk for the development of CBC (26,39). Multiple studies have shown that
CHEK2*1100delC germline mutation increases the risk for the development of BC about two-fold. First- degree relatives of BBC who carried this mutation had an eightfold increase for the
development of BC (44).
In a meta-analysis conducted by Weischer et al., they included 26,000 BC patients worldwide and analyzed the association of particular germline mutation, CHEK2 c.1100delC, and its risk for developing BC. In this type of germline mutation, there was an increased 3-to 5-fold risk for the development of BCYW. Homozygous women with this mutation have a significantly higher risk for BC in comparison to heterozygote women. In this study, they also concluded that among Pakistani young women, the rate of this mutation was at low frequency. Furthermore, they added that in
Pakistan, there are two more missense mutations (p.H371Y and p.D438Y) related to BC. In the Polish population, the CHEK2 p.I157T was associated with an increased risk of 1.5 folds for the development of BC; this risk was doubled in patients with a family history of BC (20).
In a Chinese study, they searched for potential CHEK2 variants that will cause an increased risk for the development of BCYW, and they sequence exon 10 of CHEK2 from the blood of 150 Chinese BC Patients from whom were 136 BCYW. They studied the mutation Y390C variant in young high-risk BC patients was found in 8% (12 of 150) (20,33), and 2 in 250 healthy controls. Out of the 12, 4 had a family history of BC. In patients without a family history, this mutation carriers tend to
develop early BC. In this study, they identified a novel CHEK2 allele but also showed that this allele impairs CHEK2 function during DNA damage response (33).
In a different study analyzing the Pakistani population, it was reported that only 20% of BCYW had mutations in high penetrance genes (BRCA1, BRCA2, TP53), this leads the scientists to believe that there are other genes with genetic susceptibility of BC in Pakistani women. They analyzed the CHEK2 gene mutation. They identify five deleterious recurrent mutations that confer an increased risk of two-folds for the development of BC (CHEK2 c.1100delC, p.I157T, p.S428F, c.IVS2 +1G>A, and del5395). In their study, they observed that the carriers of the c.1100delC mutation had an increased risk of 3-to 5-folds for the development of BCYW. In their study, they concluded that the CHEK2 germline mutations play a negligible role in BCYW in the Pakistani population.
Furthermore, in the Asian population, the CHEK2 germline mutations are not well defined since most of their studies included only the c.1100delC mutation (46).
In the Finnish population, two CHEK2 variants, c.470T > C and c.1100delC, were reported to be identified in 10 of 82 (12.1%) BCYW. It was shown that the c.1100delC variant confers an elevated two-fold risk for the development of BC, whereas c.470T >C variant is conferring a lower risk for the development of BC.Eight women were heterozygous to the c.470T > C variant. Two of the previously mentioned had bilateral BC. Three women were detected with a heterozygous c.1100delC variant. One BCYW carrying c.1100delC variant also carried the c.470T > C variant. Another patient, in this study, had bilateral BC at the age of 44 and a family history of BC (mother and father’s sister). A third patient with the c.1100delC variant had BC diagnosed at the age of 45 years and one affected individual (mother) in her family. In conclusion, CHEK2 mutations, c.470T > C,
and c.1100delC variants contribute significantly (12.2%) to these high-risk individuals, but further study is needed (31).
In a study analyzing the pathogenic variants (which are associated with the risk of hereditary BC) in genetically heterogeneous cancers was found that PVs were found in 9.3% of patients in which CHEK2 mutation was found in 11.7% of BCYW. Among other BCYW with different cancer subtypes, the positive rate was lower than observed for women with TNBC (12.1%-16.3%) (38). In a study about the Italian family, the researchers described this family as having a high number of BC cases related to CHEK2 deletions and duplications mutations. They identified a new 23-kb duplication mutation in the CHEK2 gene; the mutation was extending from intron 5 to 13 and was associated with BC in the family. Duplication mutations are infrequent and can confer a high susceptibility for the development of BC (45).
In conclusion, genotyping screening for CHEK2*1100delC with BRCA1 and BRCA2 mutations should be considered in women with a family history of BC. Another common mutation c.1111C4T (p.H371Y) also plays an active role in the development of the BC (44). The clinical management of CHEK2 mutation is still not yet available (47).
Other genes related to BCYW:
HER2 is also known as c-erbB-2, is located on the long arm of human chromosome 17 (17q12). The expression of this gene is activated mainly through gene amplification and re-arrangement. The HER2 protein is an epidermal growth factor receptor (EGFR) of a tyrosine kinase family and form heterodimers with other ligand-bound EGFR family members such as HER3 and HER4, thus, it activates downstream signaling pathways. Overexpression of HER2 is detected in about 20% of primary BC (3,4).
HER2 appeared to be different in younger patients and are more likely to harbor a genetic
predisposition (8). HER2 positive breast cancer accounted for 20% of all breast cancer patients. The identification of its pathway and its dysfunction has led to the development of antiHER2 monoclonal antibody (mAb), trastuzumab. Trastuzumab treatment with chemotherapy significantly improves overall survival in the metastatic and adjuvant stages (4).
FGD3 is a gene located in the long arm of chromosome 9, and it works as a cell migration inhibitor in both standard and malignant cells and seems to have an indicator of the outcome of breast cancer. In a study, it was evaluated the relationship between the prognostic factors, FGD3 expression, and the outcome in BCYW. It was found that the lower FGD3 expression decreased the probability of disease-free survival and overall survival. Moreover, low FGD3 expression increased the risk of death from breast cancer and was associated with a widespread lymph node involvement (more than 10 lymph nodes). In this study, they showed the FGD3 is an independent prognostic factor in
BCYW. Furthermore, BCTW had a higher percentage of HER2 positive tumors (24.5% vs. 13-15%), and triple-negative tumors (16.3% vs. 11.2%) compare to the general population. In contrast, the incidence of ER-positive tumors was the same in all ages of the population (48).
EGFR is also known as c-erbB-1 or HER1 in humans, is located on the short arm of chromosome 7 (7p12). Overexpression of EGFR is found in more than 30% of cases of inflammatory breast cancer, which is a very aggressive subtype of breast cancer. Patients with EGFR-positive have a poorer prognosis than those with EGFR-negative tumors (3).
12. CONCLUSION
1. Carriers of BCRA1 and BRCA2 gene mutations are at extremely high risk for the development of breast cancer, an increased risk of about 20-25 percent in lifetime risk for the development of
primary breast cancer, depending on population. Of breast cancer in young patients, 7% have BRCA1 mutation characteristics with ER-negative and HER2- negative tumors. BRCA2 is associated with high-grade invasive ductal carcinomas, ER-positive, and p53- negative.
2. TP53 gene mutation is high- penetrance mutations; they are mainly HR-positive, HER2-positive tumors. They account for 50% of breast cancer cases regardless of age. The frequency is up to one-third in young patients with breast cancer depends on the population. Furthermore, a mutation in this gene is related to Li-Fraumeni syndrome, which has an increased risk for the development of many human cancers. In Li-Fraumeni syndrome, breast cancer in young patients is about 25-30%.
3. CHEK2 gene mutation is considered a moderate penetrance gene. It presented mainly in younger patients with breast cancer. The most common CHEK2 gene mutation is CHEK2*1100delC, which plays an active role in the development of breast cancer in young women. CHEK2*1100delC
germline mutation increases the risk for the development of breast cancer from two-to five-folds, and its prevalence differs in different populations.
13. PRACTICAL RECOMMENDATIONS
There is a lot known about the BRCA1 and BRCA2 mutations, but less is known about TP53 and CHEK2 mutations. More studies are needed in the field of BCYW with TP53 and CHEK2 mutations, mainly in the treatment options.
Genetic consultation should be given to any young woman who develops BC before the age of 55 with or without a family history of BC or any cancer-related syndrome. In the case of a harmful BRCA1 or BRCA2 mutations, a thorough investigation should be given with the focus on TP53 or CHEK2 mutations.
We should consider new prevention plan for women with family history but without the development of BC as a protective measurement.
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