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Clinical Genetics: Risk Assessment, Screening and Genetic Testing for Inherited Susceptibility for Cancer Mollie L. Hutton, MS, CGC Certified Genetic Counselor Clinical Genetics Service, RPCI [email protected] Genetics is everywhere… Health care & medical literature Mainstream media TV, newspapers, magazines Direct to consumer marketing of gene tests Careers: bioinformatics, agriculture, business, forensics, military Guidelines & standards of practice developed General Principles Causes of cancer Inheritance Patterns Importance of diagnosing a genetic disorder Cancer genetic risk assessment Inherited Cancer Syndromes 5%-10% Hereditary 20% - 25% Multifactorial 70% Sporadic All cancer is genetic, not all cancer is inherited Cancer Associated Genes: Inheritance Patterns Normal “Unaffected” Carrier + Carrier, affected Sporadic + Gene mutation inherited in autosomal dominant manner (e.g., BRCA1), but expression may be at AD level (e.g, oncogene) or AR level (e.g, tumor suppressor gene) Individuals may inherit altered gene, but not have phenotype (ie, reduced penetrance) Importance of diagnosing a genetic disorder Impacts Medical management Screening/surveillance For individual and family Possible risk for another diagnosis Options for prevention Participation in research Family planning Genetic Counseling Clinical consultation involves: Genetic risk assessment (cancer & non-cancer) individual & family hx review of med records physical exam Genetic counseling: ■ inheritance pattern ■ risk models ■ medical management options ■ genetic testing ■ ethical/legal/psychosocial issues ■ support decision/facilitate adjustment Work in conjunction with other clinic/s, or separate Risk Assessment Obtain at least a 3 generation family history (if possible) Maternal & Paternal family history are equal in importance Confirm diagnoses (if possible) Medical records, death certificates, etc. Consider Environmental exposures Ethnicity/racial background Constellation of cancers Personal and Family History Early age onset Multiple primary cancers Bilateral cancers Rare cancers Cancer with no identifiable risk factor Positive family hx of same cancers Family hx of cancers/conditions that occur together in syndromes Pancreas d. 62 Prostate, 68 dx 62y Breast, dx 45 d. 89 86 Breast, dx 52 Ovary, dx 59 d. 60 71 36 R Breast, dx 32 L Breast, dx 36 Breast, dx 59 Importance of Family History Before genetic testing was available, family history was used to identify “high risk” families Still used in cases where mutation not identified Clinical diagnostic criteria applied to HOWEVER, family history is not fool proof: De novo mutations Ex. FAP Reduced penetrance Ex. BRCA in small family or family with few females Examples of Cancer Syndromes ~70% Sporadic Hereditary breast and ovarian ca BRCA1, BRCA2 Li-Fraumeni syndrome p53 Cowden syndrome PTEN Peutz-Jeghers syndrome STK11 Hereditary nonpolyposis MLH1, MSH2, MSH6, colorectal ca Familial adenomatous polyposis PMS2 APC Multiple endocrine neoplasia 2 Multiple endocrine neoplasia 1 RET MEN1 Hereditary Diffuse Gastric Cancer CDH1 Multifactorial 5%–10% Hereditary Breast Cancer: Associated with Different Genetic Syndromes Syndrome HBOC Associated Cancers/Traits Chr./Gene breast (both female & male), ovarian, 17q21.1/ BRCA1 13q12-13/ BRCA2 prostate, pancreas, melanoma Li-Fraumeni breast, sarcomas, brain tumors, leukemia, adrenocortical cancer breast, thyroid & endometrial ca, macrocephaly, structural thyroid probs, lipomas, hamartomas Cowden Peutz Jegher breast & pancreas ca, GI polyps, sex cord tumors 17p13/ p53 10q22-23/ PTEN 19p13.3/ STK11 Ex. changes in tstg technology & criteria Hereditary Breast Cancer: Cowden Syndrome Associated w/ mutations in PTEN Characteristics Cancers: breast; thyroid (follicular); endometrial fibrocystic breast disease and uterine fibroids macrocephaly mucocutaneous lesions lipomas / fibromas trichilemmomas Penetrance (lifetime risk) breast cancer: 25-50% for women thyroid cancer: ~10% endometrial cancer: 5-10% Clinical diagnostic criteria established to make diagnosis www.infocompu.com/.../images/s_cowden1.jpg www.uveitis.org/images/Image1.jpg Common Cancer Syndromes ~70% Sporadic Hereditary breast and ovarian ca Li-Fraumeni syndrome Cowden syndrome BRCA1, BRCA2 P53 PTEN Peutz-Jeghers syndrome STK11 Familial adenomatous polyposis APC Hereditary nonpolyposis colorectal ca MLH1, MSH2, MSH6, PMS2 Multiple endocrine neoplasia 2 Multiple endocrine neoplasia 1 RET MEN1 Hereditary Diffuse Gastric Cancer CDH1 Multifactorial 5%–10% Hereditary Familial Adenomatous Polyposis: FAP mutation in APC gene (a tumor suppressor) autosomal dominant, nearly 100% penetrant 30% new mutation rate patients develop 100s – 1000s of colon polyps, some of which become malignant Also risk for desmoids, CHRPEs, hepatoblastoma attenuated form (AFAP) with typically <100 polyps genotype/phenotype correlation exists dro.hs.columbia.edu/vr6/beartracksa.jpg Hereditary Non-Polyposis Colorectal Cancer: HNPCC 80% lifetime risk for colorectal cancer early age of onset (45y average) excess of proximal (right-sided) tumors multiple primary colorectal tumors polyps progress to tumors 100-1000x more rapidly than do sporadic colon polyps presence of extracolonic tumors: uterine (60%) ovarian (12%) gastric (13%) renal pelvis (3%) Clinical Criteria: Amsterdam Criteria 3 affected family members in which two are first degree relatives of the third in two generations and one of them had colon cancer at <50 years of age Common Cancer Syndromes ~70% Sporadic Hereditary breast and ovarian ca Li-Fraumeni syndrome Cowden syndrome BRCA1, BRCA2 P53 PTEN Peutz-Jeghers syndrome STK11 Hereditary nonpolyposis MLH1, MSH2, MSH6, colorectal ca Familial adenomatous polyposis PMS2 APC Multiple endocrine neoplasia 1 Multiple endocrine neoplasia 2 MEN1 RET Hereditary Diffuse Gastric Cancer CDH1 Familial 5%–10% Hereditary Multiple Endocrine Neoplasia Type 1 MEN1 Pituitary tumors Parathyroid tumors Endocrine tumors of the gastro-entero-pancreatic tract gastrinoma, insulinoma, glucagonoma 90% symptomatic by mid-20s 10% new mutation rate endocrine.niddk.nih.gov/pubs/men1/images/men.gif Multiple Endocrine Neoplasia Type 2 MEN2A Medullary thyroid cancer -- occur in ~95% of cases Pheochromocytoma -- occur in ~50% of cases Parathyroid disease -- occur in ~20-30% of cases MEN2B Medullary thyroid cancer -- occur in 100% of cases Average onset by age 15-20 Average onset in early-childhood Pheochromocytoma – occur in ~50% of cases Mucosal neuromas Marfanoid body habitus FMTC Medullary thyroid cancer -- occur in 100% of cases Average onset in middle-adulthood Common Cancer Syndromes ~70% Sporadic Hereditary breast and ovarian ca Li-Fraumeni syndrome Cowden syndrome BRCA1, BRCA2 P53 PTEN Peutz-Jeghers syndrome STK11 Hereditary nonpolyposis MLH1, MSH2, MSH6, colorectal ca Familial adenomatous polyposis PMS2 APC Multiple endocrine neoplasia 1 Multiple endocrine neoplasia 2 MEN1 RET Hereditary Diffuse Gastric Cancer CDH1 Familial 5%–10% Hereditary Hereditary Diffuse Gastric Cancer (HDGC) CDH1 gene – only gene known to be associated w/ HDGC; however accounts for only 1/3 of hereditary diffuse gastric cancers CDH1 mutations confer: Increased risk for diffuse gastric cancer 67% lifetime risk for men 83% lifetime risk for women Increased risk for lobular breast cancer (39% lifetime risk) Majority of cancers diagnosed before age 40 Differential Diagnosis: Cancer Syndromes brain ovary H H prostate B P O C C sarcoma Li Fr au m en i renal colon breast Tu rc ot H N P C C polyps F A P P J Benign tumors eye M E N endometrial thyroid Overlap in cancer syndromes Must consider all possibilities – then determine most likely Also take into consideration benefit of identifying one syndrome over another as it relates to medical management options Common Genetics Terms Genotype Phenotype Expression Pleiotrophy Penetrance Phenocopy Genotype vs. Phenotype Same genotype (genetic makeup) different phenotype (observed features) Pleiotropy (single gene influences multiple phenotypic traits) Ex. MLH1 assoc. w/ colon ca, endometrial ca, ovarian ca, ureter ca, etc. Expression (different degrees of presentation) Ex. APC – classic vs. attenuated Same phenotype different genotype Ex. Breast cancer assoc. w/ mutations in BRCA, PTEN, p53 Genotype vs. Phenotype Phenocopy = Normal genotype with disease phenotype VS Penetrance = Mutant genotype with no disease phenotype Thus, susceptibility (rather than predisposition) Majority of hereditary cancer syndromes are NOT 100% penetrant Genetic Testing Why? Explanation for cancer Clarify personal cancer risks Determine appropriate screening/management Preventive options Treatment options following dx Chemopreventive, surgical Identification of at-risk family members Potentially rule out inherited risk Genetic Screening & Testing: Important Considerations Who to test? Clinical vs Research testing Type/Method Biochemical – protein product Cytogenetic – all/part of chromosome Molecular – gene/DNA/RNA Results: sensitivity, specificity Result interpretation: +,-,VUS negative vs true negative Genetic Screening & Testing (continued) IMPORTANTLY – can test for lots of things, but cannot interpret many things If cannot clarify cancer risk based on presence of mutation and/or cannot screen for or manage increased cancer risk, is genetic testing justified? Ex. PALB2 Pros and cons of testing PROS: identifies those at high risk and those not at high risk option of increased surveillance/prophylactic surgery relief from anxiety appreciate risk to children opportunity to be proactive in making medical and lifestyle choices Pros and cons of testing CONS: negative results may be meaningless or falsely reassuring often no proven interventions increases anxiety psychological burden – fear, guilt, etc. impact on family dynamics cost & availability Common misunderstandings regarding genetic testing Testing not covered by insurance Risk for discrimination Extension HIPAA GINA of Civil Rights Act Genetic Testing of Minors: Issues When is it appropriate? Not for adult onset disorders (Fryer, Arch Dis Child, „00) Parental choice vs child‟s choice: consent vs assent Potential harms stigmatization negative effect on family & interpersonal relationships; different view of child self-concept; psych risks (Grosfeld, Pt Educ/Coun, „97) “shall only be tested when ...for ...purpose of better medical care” (WHO document, 1998) Other applications of genetics DNA Banking Pharmacogenetics DNA Banking Allows an individuals DNA to be saved for future genetic testing Important in situations where genetic testing is not currently available due to limitations in knowledge/technology or when a patient is terminally ill and there is no time for traditional genetic evaluation Pharmacogenetics & CRC Patients with colon cancer may be treated with a chemotherapy agent called irinotecan Some UGT1A1 gene polymorphisms predispose to irinotecan toxicity Genotyping can identify those at high risk for toxicity and who may be better treated with a different agent