BRCA Gene Family at Age 20. Considering the Impact

Size: px

Start display at page:

Download "BRCA Gene Family at Age 20. Considering the Impact"

Jane Ward
6 years ago
Views:

1 BRCA Gene Family at Age 20 Considering the Impact

2 What Have We Learned About Breast Cancer from BRCA Genes?

3 Introduction What did we learn over the past 20 years? Learn about BRCA genes? Learn about breast cancer? Learn about ourselves? How would we score the impact of BRCA genes Micro individual family? Macro global implications?

4 BRCA Gene Family Natural tendency towards the entropy of cancer in humans Rapid genetic drift Complex family of diseases Phenotype is family specific not mutation specific Ethical issues of Gene patenting Genetic discrimination/genetic exceptionalism Cultural/Religious impediments to testing Pre-implantation Genetic Diagnosis (PGD) Direct to consumer marketing Pre-implantation genetic testing Created conceptual frameworks to understand gene function

6 Hitting the Two Hit Hypothesis Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele. loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. King TA, Li W, Brogi E, Yee CJ, Gemignani ML, Olvera N, Levine DA, Norton L, Robson ME, Offit K, Borgen PI Ann Surg Oncology 2007

7 BRCA: The Haploinsufficient Phenotype Biallelic inactivation of cancer susceptibility gene BRCA1 leads to breast and ovarian carcinogenesis. Paradoxically, BRCA1 deficiency results in early embryonic lethality, To survive homozygous BRCA1 inactivation during tumorigenesis, precancerous cells must accumulate additional genetic alterations, such as p53 mutations This requirement for an extra genetic "hit" contradicts the two-hit theory for the accelerated carcinogenesis associated with familial cancer syndromes.

8 BRCA Mutation as a Cause of Genomic Instability Using somatic cell gene targeting, we demonstrated that a heterozygous BRCA1 185delAG mutation confers impaired homology-mediated DNA repair and hypersensitivity to genotoxic stress. In BRCA1 heterozygous clones and nontumorigenic breast epithelial tissues from BRCA mutation carriers, FISH revealed elevated genomic instability when compared with their respective controls. BRCA1 haploinsufficiency may accelerate hereditary breast carcinogenesis by facilitating additional genetic alterations.

9 BRCA Gene Family BRCA Classic Tumor Suppressor Gene..maybe not BRCA1 is a Haploinsufficient Tumor Suppressor gene, which when lost through inheritance, increases a cell's susceptibility to acquire further mutations. Two Hit Hypothesis is a conceptual framework (metaphorical) but over simplifies the process and problem.

10 Is there a haploinsufficient phenotype in BRCA Gene mutation carriers? Young women with BRCA mutations who are athletic and avoid obesity have a reduced/delayed cancer phenotype when compared to controls. Marks/King Science 1995 Community based study from Washington D.C Genotyped participants; 120 Heterozygotes Female carriers had a life expectancy that was 6.8 years shorter; Male carriers had a 3.7 year reduction This reduction was statistically significant (p=0.024)

11 BRCA Gene Family Common Clinical Questions: In whom should I recommend testing? Threshold? How hard to I push? Should my clinical management of a cancer change? (Is breast conservation appropriate?) Is BSO enough prevention for breast cancer? Should I encourage SERMS? Is total skin sparing mastectomy appropriate? Is gene patenting a good thing? How does it impact my practice?

12 Path to the Discovery of BRCA Genes Linkage to 17q and 13q in large families Highly conserved satellites Mary Claire King

13 Jeffrey Boyd Quest for BRCA-1 Sequence Francis Collins Mary Claire King Mark Skolnick Barbara Weber

14 Scientists Identify a Mutant Gene Tied to Hereditary Breast Cancer a genetic trophy so ferociously coveted and loudly heralded that it had taken on a near mythic aura. Natalie Angier NYT, 9/15/94

16 Quest for BRCA-2 Sequence We report a partial consensus sequence of BRCA-2 to place it in the public domain. Genetic materials belong in the realm of the scientist, not the investor and as such should not be subject to patent laws M. Stratton

17 Quest for BRCA-2 Sequence We have completed the full length sequence of the BRCA-2 gene and have applied for appropriate protection under U.S. patent laws. M. Skolnick

18 ACLU and BRCA Patenting Gene patenting is a civil liberties issue because gene patents undermine the free exchange of information and scientific freedom, bodily integrity, and women's health. In granting exclusive rights to gene patent holders, the U.S. government in essence gives those patent holders complete control over those genes and the information contained within them. This interferes with a person's right to know about his or her own genetic makeup and scientists' rights to study the human genome and develop new genetic tests. Granting a monopoly on fundamental pieces of knowledge infringes on First Amendment rights, which protect the freedom of scientific inquiry and the free exchange of knowledge and ideas.

19 Are the Patents on BRCA Genes an Isolated Case? NO! A 2007 study found that 4,382 of the 23,688 human genes in the National Center for Biotechnology Information's gene database are explicitly claimed as intellectual property. 20% of human genes are patented. ACLU suing U.S. Patent and Trademark Office and Myriad Scientific Researchers, Clinical Geneticists, Patients rights are being violated; 5 million dollars in tax payer money invested in the discovery.

20 Founder Effect Mutations

BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population An estimated 1 in 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation 185delAG Prevalence ~1% BRCA1 BRCA2 6174delT Prevalence ~1.

21 BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population An estimated 1 in 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation 185delAG Prevalence ~1% BRCA1 BRCA2 6174delT Prevalence ~1.5% 5382insC Prevalence ~0.15% Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P,

22 Genetic Determinants of Hereditary Susceptibility to Breast Cancer Sporadic (93%) Unknown genes (35%) BRCA1 (35%) Hereditary (7%) TP53, LKB1, PTEN, HNPCC (5%) BRCA2 (25%)

23 BRCA mutations do not occur in sporadic breast cancers BRCA-1 is mutated in less than 1% of sporadic cancers. Frequency of Breast Cancer Attributable to BRCA1 in a Population-Based Series of American Women. Newman et al., JAMA 279: 915, 1998: BRCA-2 is mutated in less than 1% of sporadic cancers. Sequence variants identified: 5/90 (5.6%) AJ cases (all 6174delT) 1/400 (0.25%; corrected prevalence 0.37%) non-aj cases 16 rare polymorphisms or SVUS Kim P, Borgen P, Boyd J; ASCO 2003; Medical Genetics 23(9), 2004

24 BRCA1-Associated Cancers: Lifetime Risks: Family Specific Breast cancer: 50%-80% (family dependent) Second primary breast cancer: 40%-60% Ovarian cancer: 30%-40% No clear evidence for increased risk at other sites (5149 Mutation Carriers: 8 Pancreas Cancers; Ontario Cancer Study Group)

25 BRCA2-Associated Cancers: Lifetime Risks Breast cancer (40%-80%) Male breast cancer (6%) Ovarian cancer (15%-25%) Increased risk of prostate, pancreatic, gallbladder/bile duct, gastric, head and neck cancers and melanoma?

26 BRCA2-Associated Cancers: Lifetime Risks Male breast cancer (6%) >500 Fold increase in risk of breast cancer development Larger risk increase than that seen in women with BRCA-2 is responsible for 5% of all male breast cancer

27 BRCA Associated Breast Cancers BRCA1 High grade Low amount of DCIS Estrogen receptor negative Probably worse outcome Basal Epithelioid Phenotype BRCA2 Moderate to high grade Low amount of DCIS Same as sporadic Same as sporadic

28 Annual breast cancer risk (per 100 women) Adapted from Antoniou A et al. Am J Hum Genet 2003; 72:

29 Retrospective Studies of LRR in BRCA vs. Sporadic Breast Cancer Study Patients BRCA + Followup Local Recurrence Genetic Sporadic Seynaeve % 16% Pierce % 8% Haffty % 21% Bremer % 6% Delaloge % 12% Robson % 8%

30 Retrospective Studies of LRR in BRCA vs. Sporadic Breast Cancer Study Patients BRCA + Followup Local Recurrence Genetic Sporadic Garcia % 4% Robson % 8% Total patient reported experience is a retrospective analysis of less than 300 highly selected, non-randomized patients with highly variable overall treatment and follow-up. EBCTG Oxford Overview: Excess death for excess local recurrences One extra death for every four preventable local recurrences.

Genetic Exceptionalism Impediments Real or imagined Novel impediments: loss of marriageability Discrimination Real or imagined (need for chart security) Psychological sequelae Parental

31 Genetic Exceptionalism Impediments Real or imagined Novel impediments: loss of marriageability Discrimination Real or imagined (need for chart security) Psychological sequelae Parental guilt; survivor guilt; severe anxiety Insomnia; depression Testing most helpful when it changes patient life trajectory Offer not sell testing Ushered in new, controversial ethical era:

33 Conclusion

34 Questions?

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

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