Biology of hereditary breast and ovarian cancer (HBOC) L. Stuppia, Medical Genetics G. d’Annunzio University Chieti-Pescara, Italy

From Broca to BRaCA

Hereditary breast cancer

Features of hereditary BC Early onset (50% before age 40) Multiple cancers Several affected members within a family with direct trasmission (high penetrance dominant inheritance)

BRCA1 (17q12) BRCA2 (13q12)

https://myriad.com/patients-families/disease-info/breast-cancer/

Two different genes, a single disease?

BRCA2 homologs and orthologs are found in organisms across three kingdoms: animal, plant, and fungi. BRCA1 homologs and orthologs are only found in animal and plant kingdoms. The presence of BRCA1/2 genes dates back to 1.6 billion years ago

Roy et al., Nat Rev Cancer, 2016

Pedigrees of families carrying BRCA1 and BRCA2 mutations.

The pathways of BRCA1 and BRCA2

BRCA1-associated genome surveillance complex (BASC)

BRCA1 and BRCA2 function in a common pathway BRCA1 is involved in: DDR signalling checkpoint activation HR and other DNA repair processes, such as NHEJ and SSA. Conversely, BRCA2 is primarily involved in HR. The human syndromes associated with BRCA1 or BRCA2 germline mutations are almost identical, with the only common functional link being represented by the HR pathway. It seems reasonable to conclude that the HR pathway is crucial for protecting the genome and that this pathway is disrupted in tumours arising in these mutation carriers.

Pandey and Raghavan: DSB repair in mammals, 2017

Roy et al., Nat Rev Cancer, 2016

Roy et al., Nat Rev Cancer, 2016

BRCA1 and DNA repair

The different functions of BRCA1 gene

A complex: DNA repair via homologous recombination B complex: G1/S cell cycle checkpoint  C complex: G2/M checkpoint  Trapp et al., 2011

Two genes different phenotypes

Larsen et al., 2013

Roy et al., Nat Rev Cancer, 2016

Epigenetics and BRCA

BRCA1 promoter methylation found in 11 tumors, all TNBC cases, and associated with: lymphovessel invasion high nuclear grade low BRCA1 mRNA expression loss of BRCA1 protein expression was shorter overall survival

BRCA1 and miRNA

Beyond BRCA1 and BRCA2

Deleterious mutations identified in 14.6% of all patients: 11.2% BRCA1 (8.5%) andBRCA2 (2.7%). Deleterious mutations in 15 other genes detected in 3.7% of patients the majority observed in genes involved in homologous recombination, including PALB2(1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 ( 0.3% to 0.5%). Patients with TNBC with mutations: diagnosed at an earlier age higher-grade tumors than those without mutations.

Because a relatively high proportion (7 Because a relatively high proportion (7.5%) of patients with TNBC with no family history and diagnosed between age 50 and 60 years had mutations, perhaps testing of all patients diagnosed at age 60 years, or even all patients irrespective of age or family history, should be considered, especially if the cost of mutation screening were to decrease over time.

Knowledge of BRCA1/2 mutation status in a patient has gone from a research question to demonstrated clinical utility directly affecting patient care. (Lee et al., 2014)

Does genetic testing really benefit public health? These data, coupled with emerging evidence of reduced mortality following risk reducing surgeries, suggest that BRCA1/2 testing may beneficially impact cancer mortality and thus public health.

NATURE REVIEWS | CANCER, 2016