The Genetics of Breast and Ovarian Cancer Prof. Piri L. Welcsh

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1 The Genetics of Breast Piri L. Welcsh, PhD Research Assistant Professor University of Washington School of Medicine Division of Medical Genetics 1 Genetics of cancer All cancers arise from genetic and epigenetic alterations Tumorigenesis is a multi-step process 10-15% of all cancer is hereditary - Genes associated with cancer predisposition include oncogenes and tumor suppressor genes 2 Oncogenes 3 The screen versions of these slides have full details of copyright and acknowledgements 1

2 Tumor suppressor genes 4 Breast cancer family 0 Traite des Tumeurs, Paul Broca, Paris, The two-hit hypothesis 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 How much breast and ovarian cancer is hereditary? The Genetics of Breast 7 Causes of hereditary susceptibility to ovarian cancer 8 Causes of hereditary susceptibility to breast cancer 9 The screen versions of these slides have full details of copyright and acknowledgements 3

4 BRCA1 and BRCA2 mutations Autosomal Dominant Families may have breast and/or ovarian cancer 10% of epithelial ovarian cancer and 5% of breast cancer No clear relationship between specific mutation and cancer type or penetrance Factors that influence penetrance are not well identified 10 Lifetime cancer risk in mutation carriers BRCA1 Female breast: 60-85% Contralateral breast: 40-60% Male breast: increased Ovarian: 25-50% (15-25x) Pancreatic: 3-4% (2-3x) BRCA2 Female breast: 50-80% Contralateral breast: 40-60% Male breast: 7% (80x) Ovarian: 15-25% (10x) Prostate: 2-3x, increased only below age 65 Pancreatic: 2-5% (3x) Melanoma: 5% (2x) Stomach, Esophageal and Biliary 11 Epidemiology: BRCA1 and BRCA2 1/800 women will carry a mutation Founder mutations occur in many populations 12 The screen versions of these slides have full details of copyright and acknowledgements 4

5 Founder effect The Genetics of Breast 13 BRCA1 and BRCA2: selected examples of founder mutations 14 BRCA1 and BRCA2 mutations in the Ashkenazi-Jewish population 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Varied penetrance Family 1. BRCA1: 2800 AA I 6 2 csu 59 csu 57 Pr 79 Pr V N V N II 91 Br 74Br 32 Br 45 Br 36 Ov Pr Pa 66 Br Co 54 Ov 61 V N V N V N V N V N V N V N V N V N III Br Br 28 V N V N Br Br Br 41 Br 39 Br Br 34 Br 49 Br 29, 39 V N V V IV Br 25 Br NYBCS: tested consecutive Ashkenazi women with breast cancer for founder BRCA1 and BRCA2 mutations *Prevalence of ancient BRCA1 and BRCA2 mutations among 1008 NYBCS probands with invasive breast cancer BRCA1 BRCA1 BRCA2 185delAG 5382insC 6174delT Any of Low incidence family (NYBCS 96) - BRCA1.5382insC <1 breast cancer and no ovarian cancer in proband s* nuclear family * Br The screen versions of these slides have full details of copyright and acknowledgements 6

7 Family 96: BRCA1 5382insC Br 50 Br 24 Br 50 Liv 69 Br 54 * Br 34 Pan NN 77 NN Br Ov NN NYBCS revealed 10% of women carried a mutation; Half of women with mutations had no breast or ovarian cancer in a first or second degree relative 19 Risk of breast cancer for relatives with BRCA1 or BRCA2 mutations Cumulative breast cancer incidence BRCA1.185del AG BRCA insc BRCA2.6174delT All Age Risk of ovarian cancer for relatives with BRCA1 or BRCA2 mutations Cumulative breast cancer incidence Age BRCA1 BRCA BRCA BRCA2 21 The screen versions of these slides have full details of copyright and acknowledgements 7

8 Risk of breast cancer for NYBCS relatives with BRCA1 or BRCA2 mutations by birth cohort Cumulative breast cancer incidence Age Born > The Genetics of Breast Born < Factors affecting penetrance 23 Factors not significantly associated with age at breast cancer diagnosis among probands with BRCA1 or BRCA2 mutations Age at menarche Miscarriage or induced abortion Oral contraceptive use Smoking Alcohol consumption Household or occupational exposure to radiation or chemicals Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 Br Br Br Br 51 O v Pan New York breast cancer study conclusions The Genetics of Breast Risks of breast cancer in NYBCS women due to BRCA1 or BRCA2 are: by age by age Risks of breast cancer among women with BRCA1 or BRCA2 mutations are higher in recent birth cohorts Risks of ovarian cancer due to BRCA1 are: by age by age Risks of ovarian cancer due to BRCA2 are: by age by age Mutation detection for BRCA1 and BRCA2 Test proband Deleterious mutations - Usually lead to protein truncation Single amino acid substitution (Variant of Uncertain Significance) - Many are benign polymorphisms, no functional assay - Many are rare and not enough data exists to classify - Chance of identifying VUS is 8% in Caucasians, 10-15% in African-Americans and Asians - These results should not be equated with a deleterious mutation - Sequencing misses larger deletions, duplications or rearrangements (approximately 12% of deleterious mutations) 26 Inherited large rearrangements in BRCA1 and BRCA BRCA = Δex = 1829 stop Pan 57 Lung 49 Br 53 Cx 40, Lung 49St 64 Br 35, Leuk Br 57 Br 56 Ov Br V N Variant detected in BRCA1 transcript: exon 13 spliced to exon 21 -> 1829 stop Br 26 Mechanism of rearrangement? Unequal homologous recombination involving Alu repeats 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 Genomic regions of BRCA1 on 17q21 and BRCA2 on 13q kb BRCA1 exons (5' > 3') BRCA1 repeats BRCA2 exons (5' > 3') BRCA2 repeats Exon Alu CR1 L1 L2 LTR MER1 MER2 MIR Mariner Simple_repeat Other 28 Genetics of breast cancer mystery families Mystery family - High risk breast and/or ovarian cancer (4 or more cases of breast or ovarian cancer) with wildtype BRCA1 and BRCA2 based on full sequencing Risk may be attributed to: - Cryptic BRCA1 and BRCA2 mutations (The chance of finding a cryptic mutation in BRCA1 or BRCA2 is about 12%) - Moderate penetrance alleles - Low penetrance alleles 29 Inherited breast and ovarian cancer High penetrance alleles: classic autosomal dominant; cancer syndromes; high risk Moderate penetrance alleles: much lower risk Low penetrance alleles: interact with other genetic and environmental factors to impact cancer risk 30 The screen versions of these slides have full details of copyright and acknowledgements 10

11 PALB2 1592delT in Finnish breast cancer families 31 PALB2 1592delT in a Finnish prostrate cancer family 32 Genes for inherited breast cancer BRCA1 and BRCA2* - very high risk of breast and ovarian cancer P53 and PTEN - high risk of breast cancer; associated with rare cancer syndromes CHEK2, ATM, NBS1, RAD50, BRIP1*, PALB2* - moderate risk of breast cancer (1-4 fold increase) *Biallelic mutations cause Fanconi anemia 33 The screen versions of these slides have full details of copyright and acknowledgements 11

12 Breast cancer genes converge on pathways to maintain to genomic integrity The Genetics of Breast 34 Biology of breast cancer genes Expressed in most tissues: female tropic nature of cancers not known Involved in cellular response to DNA damage: DNA repair, cell cycle control, regulation of transcription 35 Identification of inherited cancer risk Changes in prevention and screening strategies, aiming to decrease morbidity and mortality Identification of cancer risk in other organs Clarification of risk to other family members 36 The screen versions of these slides have full details of copyright and acknowledgements 12

13 Helps women make informed decisions Can improve knowledge and perception of absolute risk Reduce anxiety Benefits Adverse consequences - Patient insurance and employment discrimination 37 Risk assessment Criteria to identify approximately 2% of women who should consider BRCA testing Early age at diagnosis Bilateral breast cancer History of both breast and ovarian cancer Breast cancer in 1 or more male family members Multiple cases of breast cancer Both breast and ovarian cancer 1 or more family members with 2 primary cases Ashkenazi Jewish background 38 Cancer risk reduction in women with BRCA1 or BRCA2 mutations Screening: alternate mammogram (poor sensitivity) and breast MRI (detects more cases but effect on mortality not clear) at 6 month intervals beginning age 25 Consideration of prophylactic mastectomy (decreases incidence) Oophorectomy before menopause (decreases incidence) Chemoprevention? SERMs? (selective estrogen receptor modulators)? - May decrease incidence of ER+ cancers; risks (embolism, thrombosis, endometrial cancer) *most BRCA1 breast cancer is ER- 39 The screen versions of these slides have full details of copyright and acknowledgements 13

14 Experience at surgery for preventive removal of ovaries of a healthy woman with a BRCA1 mutation The Genetics of Breast Family 431 BRCA2.2558insA Ovarian cancer in situ FT 65 Pr 65 Br Women with increased-risk family history: BRCA1/BRCA2 - (Mystery families 5% of patients had mutation in CHEK2; 1% had a mutation in p53) Other mutations PALB2? *Women with increased-risk family history but negative for BRCA1/2 may benefit from prophylactic surgery The screen versions of these slides have full details of copyright and acknowledgements 14