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

2. From Broca to BRaCA

4. Hereditary breast cancer

5. 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)

7. BRCA1 (17q12) BRCA2 (13q12)

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

9. Two different genes, a single disease?

10. 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

11. Roy et al., Nat Rev Cancer, 2016

12. Pedigrees of families carrying BRCA1 and BRCA2 mutations.

13. The pathways of BRCA1 and BRCA2

14. BRCA1-associated genome surveillance complex (BASC)

16. 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.

17. Pandey and Raghavan: DSB repair in mammals, 2017

18. Roy et al., Nat Rev Cancer, 2016

19. Roy et al., Nat Rev Cancer, 2016

21. BRCA1 and DNA repair

23. The different functions of BRCA1 gene

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

29. Two genes different phenotypes

30. Larsen et al., 2013

31. Roy et al., Nat Rev Cancer, 2016

32. Epigenetics and BRCA

34. 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

35. BRCA1 and miRNA

38. Beyond BRCA1 and BRCA2

39. 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.

40. 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.

44. 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)

45. 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.

46. NATURE REVIEWS | CANCER, 2016