Focus sul test BRCA
SANDRO ORRU’
Dipartimento di Scienze Mediche e Sanità Pubblica Università degli Studi di Cagliari SC. Genetica Medica ATS Sardegna Ospedale Binaghi, Cagliari
OC subtypes: mutations
Romero I et al. Endocrinology 2012; 153: 1593-1602
OC subtypes: mutations
Looking for BRCA 1 and BRCA 2
1990s Localisation of the breast cancer susceptibility gene (BRCA1) on 17q12‒212
1994
1995
Smith SA, et al. Genes Chromosomes Cancer. 1994;10:71‒6.
Miki Y, et al. Science 1994;266:666‒671.
Futreal PA. Science. 1994;266:120‒122.
Wooster R, et al. Science 1994;265:2088‒90.
Wooster R, et al. Nature 1995;378:789‒792.
BRCA2 localised to chromosome 13q12‒135
1994 Identification of BRCA1 by US scientists3
BUT BRCA1 mutations accounted for:4
• Most, but not all, families with many cases of both early onset breast and ovarian cancer that set
• Just under half of all families affected by multiple breast cancer cases
• But no families affected by both male and female breast cancer
Identification of BRCA2 by UK scientists6
Search for BRCA2
What is the function of BRCA 1 and BRCA 2 ?
Tumor suppressor genes involved in DNA repair Autosomally transmitted (chromosomes 17 and 13)
When mutated: higher incidence of hereditary breast and ovarian cancer (HBOC syndrome)
What is the function of BRCA 1 and BRCA 2 ?
HOMOLOGOUS RECOMBINATION
What is the function of BRCA 1 and BRCA 2 ?
Impairment of BRCA1 and BRCA2 function leads to
DNA instability, telomere shortening and higher risk of endocrine related cancer (breast and ovary)
Risk of Breast Cancer in BRCA 1/2 carriers
Risk of Ovarian Cancer in BRCA 1/2 carriers
Reasons to perform BRCA1/2 test in ovarian cancer patients
• Identification of unaffected mutation carriers
• Prognostic importance/prediction of tumor behaviour
• Impact on patient treatment
- Platinum sensitivity
- Sensitivity to intraperitoneal chemotherapy - Sensitivity to other chemotherapy
- Pegylated liposomal doxorubicin - Trabectedin
- PARP inhibition
Reasons to perform BRCA1/2 test in ovarian
cancer patients
Perché eseguire il test BRCA nelle donne con carcinoma ovarico ?
La presenza di varianti patogenetiche BRCA è un fattore prognostico favorevole
BRCA1
BRCA2
Huang 2017. Association of BRCA1/2 mutations with ovarian. An updated meta-analysis. Medicine (Baltimore). 2018, 97(2) Medicine (Baltimore). 2018 Jan;97(2)
Bolton, JAMA 2012
Impact of BRCA1/2 germline mutations on survival
Kaye SB, et al. J Clin Oncol 2012
BRCA status and response to chemotherapy
• 42% platinum resistant; 58% partially platinum sensitive
Monk , et al. Ann Oncol 2015
• OVA-301 phase III study in recurrent ovarian cancer
• PLD +/- trabectedin
Mechanisms of chemosensitivity in BRCA carriers
• At least 25% of BRCA 1-2 mutation carriers are >60 yrs old
• Approximately 35%-40% of BRCA 1-2 mutation carriers do not have a family history of cancer
• Histologic type (except mucinous) is not a sufficient criterion for BRCA testing
BRCA mutation is not limited to younger patients, with family history and high grade histotypes
Malander S, et al. European journal of cancer 2004;40:422-8; Risch HA, et al. Journal of the National Cancer Institute 2006;98:1694-1706.; Soegaard M, et al. Clinical cancer research 2008;14:3761-3767; Walsh T, et al. Proceedings of the National Academy of Sciences of the United States of America 2011;108:18032-18037; Alsop K, et al. Journal of clinical oncology 2012;30:2654-2663.; Song H, et al. Human molecular genetics 2014;23:4703-4709.
BRCA mutation can be germline or somatic
BRCA mutation can be germline or somatic
Germline BRCA test
Alsop K, et al. J Clin Oncol 2012; 30: 2654–63.
BRCA mutation frequency in 1001 patients with non mucinous ovarian cancer
14.1% of the studied population
6.3% of clear cell subtype
8.4% of endometrioid subtype
16.6% of serous histotype
17.1% of high grade serous subtype
Germline BRCA mutation detected in:
15.6% <40 yrs old
24.2% 41-50 yrs old
17.1% 51-60 yrs old
8.3% >60 yrs old
44% with no family history of both ovarian and breast cancer
Somatic BRCA test
Somatic BRCA test
Somatic BRCA test
BRCA mutational status evaluation
In which patients?
BRCA mutational status (either somatic o germline) should be evaluated in all patients with non mucinous OC diagnosis.
When?
Ideally at diagnosis, to complete the diagnostic step to both provide information for therapeutic choices and implement access to genetic counseling for screening.
OC+BC 10%
BC 88%
Altri 2%
BRCA Accesso al test Germinale
Le pazienti con carcinoma ovarico epiteliale (esclusi borderline o mucinosi).
Le pazienti con BC
Casi familiari 2 affetti (1°grado)
•Ca mammella<50+Ca mammella
•Ca mammella <50+Ca ovaio/tube/peritoneo
•Ca ovaio/tube/peritoneo +Ca ovaio/tube/peritoneo
•Ca mammella +>Ca pancreas, prostata
•Casi familiari con 3 affetti (1°grado) Casi Sporadici
•Ca mammella <45 anni o <60 anni se TNBC
•Ca ovaio, tube, peritoneo <50anni
•Tumori primitivi multipli (bilaterale mammella, mammella e ovaio/tube/peritone/
•Ca mammella maschile
Le mutazioni di BRCA1 e BRCA2 spiegano solo una parte dei casi.
Dati riferiti a 1105 Test BRCA analizzati presso il
laboratorio di Genetica Molecolare SC Genetica Medica, Ospedale Binaghi, Cagliari
OC+BC 10%
BC 88%
Altri 2%
Accesso al test BRCA Germinale
BRCA1
6% BRCA2
3%
91%
Mutazioni Patogenetiche BRCA nel tumore della mammella
BRCA1 21%
BRCA2 4%
75%
Mutazioni Patogenetiche BRCA nel tumore ovarico
Kroeger & Drapkin Curr Opin Obstet Gynecol. 2017 29:26-34.
Variabilità somatica nel tumore dell’ ovaio sieroso di alto grado
De Picciotto et al. Critical Reviews in Oncology/Hematology, Volume 101, 2016, 50–59
Diversi geni di HRD Repair sono mutati nel BC e OC
European Journal of Cancer 69 (2016) 127e134
Seminars inOncology44(2017)187–197
Presentazione
del caso Test genetico?
Istotipo
Test BRCA (Somatico)
Se CO sieroso di alto grado, carcinoma peritoneale, o delle tube.
Se positivo
Consulenza Genetica pre-test (mini-consulenza)
Test BRCA mutazione specifica (germinale)
Target Therapy PARP inibitori
Consulenza Genetica Post-test
Estensione del test ai familiari
Percorso diagnostico per il test BRCA in ambito di Target Therapy con gli inibitori PARP
Interpretazione delle varianti.
La definizione della variante osservata deve essere effettuata secondo standard internazionali
(nomenclatura HGVS)
Ciascuna variante deve essere registrata.
Schema di classificazione a 5 classi
- Patogenetica (causativa; classe 5)
- Probabilmente patogenetica (classe 4)
- Di incerto significato clinico (“VUS”; classe 3) - Probabilmente benigna (classe 2)
- Benigna (classe 1)
L’INTERPRETAZIONE DELLE VARIANTI DI SEQUENZA IN GENI DI PREDISPOSIZIONE A TUMORI: INDICAZIONI OPERATIVE PER IL LABORATORIO DIAGNOSTICO
