The Role of Genetics in Ovarian Cancer Screening. Dawn DeLozier, Ph.D. Medical Geneticist, SAMC Associate Professor UCSF-Fresno
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1 The Role of Genetics in Ovarian Cancer Screening Dawn DeLozier, Ph.D. Medical Geneticist, SAMC Associate Professor UCSF-Fresno
2 How Much Breast and Ovarian Cancer Is Hereditary? 15%-20% 5%-10% Breast Cancer Sporadic Family clusters Hereditary 5%-10% Ovarian Cancer
3 Hereditary ovarian CA links, ca OVARIAN CANCER BRCA 1-2 TP53 (LFS) BREAST CANCER Colon cancer; Endometrial cancer Lynch syndrome (HNPCC)
4 Why has genetic testing (and clinical genetics) changed so much in the past 10 years? The Human Genome Project (the technology that allowed it and the results which came out of it)
5 V A R I A T I O N!! The spice of life and the bane of genomic medicine G E N O M I C S
6 GENOMICS : The study of variation between individuals We have 3 billion base pairs of DNA (3,000,000,000! A meter of DNA in each cell.) Humans are 99.9% identical in their DNA constitutions On the average 1/1000 bps differs between two individuals = 3,000,000 differences between two humans Most variation is normal (differences by ethnicity!) Variation is just as frequent in disease genes! Humans and chimps are 99% identical
7 Variation affects treatment response Constitutional gene variants (functions differently, subtle.) ex. KRAS mutation and chemo-resistance in colorectal cancer Acquired gene mutations (in affected tissues) BRC-ABL oncoprotein in CML (imatinibresponsive) EGFR mutations in lung cancer (responsive to EGFR inhibitors) The image part with relationship ID rid2 was not found in the file.
8 It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity Charles Dickens, A Tale of Two Cities
9 We know so much about the genome! We are realizing how little we really understand about the genome! Genetics has become a mainstream discipline -- Serious lack of trained professionals -- Widening knowledge gap among health care providers -- Reimbursement has not followed The Public knows a lot! Patients demand tests and answers So Many Tests Available So many test results and many incidental findings Genetic testing can lead to preventative care Translation into clinical care, and payment, lag!
10 Updated February 26, ,393 Tests 4,145 Disorders 4,722 Genes 645 Laboratories 1,066 Clinics Disorders for which genetic tests are available and laboratories offering tests,
11 Types of genetic tests Single gene analysis Sequencing AND del/dup analysis Based on clinical diagnosis ( rule out.) Targeted multi-gene panel Small vs. large panels Based on differential diagnosis Genomic scans: microarrays, whole exome or whole genome scans Non-targeted search
12 Next-generation cancer panels
13 Possible test results include (for each gene tested!) Positive for a deleterious mutation(s) Genetic variant(s) of uncertain significance A gene alteration(s) is found but cancer risk has not yet been determined with certainty. No mutation detected No mutations are found in these genes.
14 Illustrative case histories will be presented here
15 How Much Breast and Ovarian Cancer Is Hereditary? 15%-20% 5%-10% Breast Cancer Sporadic Family clusters Hereditary 5%-10% Ovarian Cancer
16 SOMATIC mutations in Ovarian cancer CTNNB1 adherence junction protein CDH1- cell adhesion molecule OPCML cell adhesion molecule PIK3CA- protein binding coupler PRKN ligase in protein degredation AKT1 protein kinase, oncogene
17 Hereditary ovarian CA links, 2015? BREAST CANCER BRCA 1-2; OVARIAN CANCER BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, RAD51D GASTROINTESTINAL & GENITOURINARY cancers Lynch syndrome (HNPCC) MLH1, MSH2, MSH6, PMS2 EPCAM Susceptibility loci on 13q13; 17q12; 17q21; 17q22 Many cancers: Li- Fraumeni TP53; CHEK2 Peutz-Jaeghers?
18 Tests for my ovarian cancer patient? BRCA 1-2 alone (8 labs in US today 9 tomorrow!) ** TARGETED MULTIGENE PANELS (6-18 genes) -- by site (e.g. ovary or kidney) -- by system or tumor type (e.g. gynecological, paraganglioma) CANCER PANELS (25-52 genes) - up to 50 labs offer
19 The bottom line A diagnosis of ovarian cancer should always lead to consideration of genetic consultation and/or testing The test recommended should take into consideration personal and family cancer history, tumor histology, financial coverage and genetic counseling components
20 References & Resources Minion LE et al (2015) Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2, Gynecol Oncol in press. Ketabi Z et al (2014) The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer. Gynecol Oncol 133: Jervis S et al (2014) Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants. J Med Genet 51: Milne RL & Antoniou AC (2011) Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. Ann Oncol 22 suppl 1:i11-7. National Ovarian Cancer Coalition (ovarian.org) Bright Pink (brightpink.org) Lynch Syndrome International (lynchcancers.org) FORCE (facingourrisk.org) National Society of Genetic Counselors (nsgc.org) American College Medical Genetics (acmg.net)
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