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GENETIC COUNSELING AND TESTING FOR CANCER Kayla York, MS, LCGC Licensed Genetic Counselor Avera Cancer Institute Outline Genetic Counseling Cancer Genetics Breast/Ovarian Cancer Colon/Endometrial Cancer Summary Genetic Counseling Genetic Counseling Genetic counselors are health professionals with specialized graduate degrees and experience in the areas of medical genetics and counseling. Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates: Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counseling to promote informed choices and adaptation to the risk or condition. National Society of Genetic Counselors, 2005 Genetic Counseling Cancer Genetic Counseling Educate patients and their families as well as provide emotional support: Cancer risks Options for genetic testing Options for cancer screening Genetic Counseling Initial Visit Personal History Family History (both mother’s and father’s side) Risk Assessment Discussion of genetics and specific genes Discussion of possible test results Discussion of impact of genetic testing Insurance/GINA Arrange testing as needed Result Disclosure Follow-up visits as needed Cancer Genetics Cancer Genetics Cancer Genetics Cancer Genetics Cancer Genetics High Risk Genes Low Risk Genes Sporadic Lifestyle and Environment Lifestyle and Environment Lifestyle and Environment Genetics Genetics Cancer Genetics Cluster of specific types of cancers/ same cancer Young ages at diagnosis Individuals with multiple or bilateral cancers Rare cancers Pattern of inheritance in the family Certain ethnic groups have higher frequencies of specific genetic disorders Cancer Genetics BRCA1/BRCA2: Breast and Ovarian Lynch Syndrome: Colorectal, Endometrial, GI Other Syndromes Familial Adenomatous Polyposis (FAP): Colon polyps, Colorectal, Stomach and Pancreatic MEN1: Parathyroid, pituitary, pancreas MEN2: Medullary thyroid Cancer Li Fraumeni Syndrome (Tp53): soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma RET: Medullary thyroid, pheochromocytomas, parathyroid adenomas Cowden Syndrome (PTEN): Breast cancer, uterine cancer, thyroid cancer, benign findings (colon polyps, thyroid nodules, macrocephaly, etc) Peutz Jeghers Syndrome (STK11): Colon polyps, breast cancer, pancreatic cancer, colon cancer, ovarian cancer, germ cell cancers Hereditary Diffuse Gastric Cancer and Lobular breast cancer (CDH1): Gastric cancer and lobular breast cancer MYH- Associated Polyposis: Colon polyps, Colorectal cancer Breast and Ovarian Cancers Breast Cancer Most common cancer in women 1 in 8 women will develop breast cancer in their lifetime 1 in 1000 men will develop breast cancer in their lifetime 5-10% of all women with breast cancer carry an inherited genetic predisposition 15-20% of all men with breast cancer carry an inherited genetic predisposition Ovarian Cancer Ovarian cancer is the 5th most common cancer for women 1 in 72 women will develop ovarian cancer in their lifetime Approximately 10- 20% of women with ovarian cancer have an inherited gene predisposition Breast and Ovarian Cancers Risk Factors- Both Age Parity Menarche (≤ 11) Menopause (≥55) Alcohol Weight Physical Activity Family History Risk Factors- Breast Previous chest radiation Hormone Therapy Breast Conditions Atypia/Hyperplasia LCIS Breast Cancer Only a fraction of breast cancers are caused by an inherited gene mutation Breast Cancer High Risk Genes Low Risk Genes Sporadic Lifestyle and Environment Lifestyle and Environment Lifestyle and Environment Genetics Genetics Hereditary Breast Cancer Predisposition Syndromes Family #1 Ovarian 40 Breast 42 Triple Neg Breast 40 Ovarian 50 Breast 38 Cancer Genetics Cluster of specific types of cancers/ same cancer Young ages at diagnosis Individuals with multiple or bilateral cancers Rare cancers Pattern of inheritance in the family Certain ethnic groups have higher frequencies of specific genetic disorders Family #1 German BRCA1 mutation Norwegian German Ashkenazi Jewish Breast 38 Ovarian 48 Breast 42 Triple Neg Breast 40 Ovarian 50 Breast 38 BRCA1 and BRCA2 BRCA1 and BRCA2 are the most common genes that predispose to breast and ovarian cancer when a mutation is present. Approximately 2-3% of women with breast cancer carry a mutation in BRCA1 or BRCA2 Approximately 10% of women with ovarian cancer carry a mutation in BRCA1 or BRCA2 BRCA1 and BRCA2 BRCA1 Lifetime risk for breast cancer 56%-80% More commonly triple negative breast cancer Lifetime risk for ovarian cancer up to 44% Lifetime risk for male breast cancer 2% Lifetime risk for prostate cancer 20% For Men and Women Lifetime risk for Pancreatic cancer 2-4% Lifetime risk for breast cancer 56%-80% Lifetime risk for ovarian cancer 11-27% For Men: For Men: BRCA2 Lifetime risk for male breast cancer 8% Lifetime risk for prostate cancer 32% For Men and Women: Lifetime risk for pancreatic cancer: 5-8% Lifetime risk for melanoma: 5% Hereditary Breast Cancer Syndromes Management: BRCA1/BRCA2 Women: Breast Cancer Breast Awareness starting at age 18 Clinical Breast Exam starting at age 25 every 6-12 months Annual Breast MRI starting at age 25 or individualized based on family history Annual Mammogram starting at age 30 or individualized based on family history Discuss prophylactic bilateral mastectomies Women: Ovarian Cancer Recommend salpingo-oophorectomy, ideally between the ages of 3540 or individualized based on family history and when child bearing is complete Data is limited but Providers can consider concurrent transvaginal ultrasound + CA-125 every 6 months starting at age 30 or based on family history NCCN guidelines 2.2016 Hereditary Breast Cancer Predisposition Syndromes High Risk Genes Cowden syndrome: PTEN Hamartoma Syndrome Breast, Uterine, and Thyroid cancers Macrocephaly and benign findings ( ex: thyroid disorders, colon polyps, and dermatological findings) Li Fraumeni Syndrome: Tp53 gene Breast, sarcoma, brain tumors, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancers Multiple primaries Diffuse Gastric cancer and Lobular breast cancer: CDH1 gene Diffuse gastric cancer and lobular breast cancer Hereditary Breast Cancer Predisposition Syndromes Moderate Risk Genes: PALB2 CHEK2 ATM These genes are well studied with lifetime risks for breast cancer of 20%-56%. They have also been shown to increase the risks for other cancers NCCN Guidelines (2.2016) Annual Mammogram and Breast MRI starting at age 30 or individualized based on family history Prophylactic mastectomy is an option with mutations in PALB2 Discussion of prophylactic bilateral mastectomies for mutations in ATM or CHEK2 is controversial and is based on family history and personal history Hereditary Breast Cancer Predisposition Syndromes Newer Genes: RAD51D BRIP1 RAD51C BARD1 RAD50 FANCC NBN MRE11A These genes are known to have an association with an increased risk for breast and other cancers but they are not as well studied and data is based on a small number of patients. The precise lifetime risks for cancers have not been determined nor have the spectrum of cancers associated with mutations in these genes. Hereditary Breast Cancer Predisposition Syndromes Family #2 d. 80s Colon 60s Polyps 83 Breast 40s Breast 44 Breast 53 d. 60s Breast 47 Endometrial 41 Endometrial 70s Family #2 d. 80s Colon 60s Polyps 83 d. 60s Breast 44 Breast 47 Breast 40s Breast 53 Endometrial 41 BRCA1/2 NEG HC: 59cm; thyroid nodules and goiter PTEN mut Endometrial 70s Cowden Syndrome: PTEN PTEN gene Tumor suppressor gene located on Chromosome 10 Responsible for control of cell division as well as other functions The exact prevalance of PTEN/Cowden syndrome is unknown Lifetime risk for breast cancer = 85% Also associated with uterine cancer, thyroid cancer, kidney and colon cancers as well as thyroid nodules, colon polyps, trichilemmomas, and macrocephaly Family #3 Prostate 55 Breast 50 Pancreatic 60 Breast 58 Breast 47 Family #3 Prostate 55 Breast 50 Pancreatic 60 Breast 58 Breast 47 BRCA2 Family #4 Breast 40 Breast 55 Breast 50 Breast 35 Family #4 Breast 40 Breast 55 Breast 50 Breast 35 BRCA1/2; TP53; PTEN; STK11; and CDH1 = NEG Family #5 Family #5 RAD51C RAD51C RAD51C is a newer gene that has been mostly associated with ovarian cancer risk Estimated to confer a 10-15% lifetime risk for ovarian cancer NCCN guidelines (2.2016) recommend consideration of risk reducing salpingooophorectomy Colon Cancer Colon Cancer 3rd most common cancer 1 in 20 individuals will develop colon cancer in their lifetime Slightly higher incidence in men than women Colon Cancer Risk Factors Risk Factors Age Smoking Phx Alcohol of colon polyps Phx of Inflammatory Bowel Disease Type 2 diabetes Diet high in red meats and processed meats Weight Physical Activity Family History Hereditary Colon Cancer Predisposition Syndromes Family #1 Col 40 Panc 60 Endo 35 Col 45 Col 40, 50 Breast 55 2 Adenomas Col 50 Endo 40 2 adenomas Family #2 Col 80 83 Col 60 2 Adenomas 1 Adenoma Colon 60 Family #3 Colectomy 40 100+ polyps # Colon 45 20 adenomas # No information Family #4 Dx 70s Dx 80 Dx 57 Dx 60 Dx 75 Dx 54 Dx 70 Colon 45 Colorectal Endometrial Bladder Dx 71 3 Dx 60 Dx 40 Dx 67 Dx 50 Dx 40s Dx 40s Pancreatic Breast Prostate Hereditary Colon Cancer Predisposition Syndromes Pt meets Bethesda criteria Pt meets Amsterdam criteria >10 adenomas in same individual Individual with multiple GI hamartomatous polyps, Juvenile polyps or serrated polyposis syndrome Individual with a desmoid tumor NCCN Guidelines 4.2013 Hereditary Colon Cancer Predisposition Syndromes Polyposis Syndromes Generally >20 colon polyps in a lifetime Non-Polyposis Syndromes Generally <20 colon polyps in a lifetime There can be overlap between the two- especially with attenuated forms of polyposis syndromes Hereditary Colon Cancer Predisposition Syndromes Amsterdam II Criteria At least 3 relatives must have a cancer associated with HNPCC/Lynch Syndrome and all of the following criteria should be present: One must be a first degree relative of the other two At least 2 successive generations affected At least one of the relatives with cancer associated with HNPCC should be diagnosed before age 50 FAP should be excluded in the colorectal cancer cases Tumors should be verified whenever possible Hereditary Colon Cancer Predisposition Syndromes Bethesda Criteria Tumors from individuals should be tested for MSI in the following situations: Colorectal cancer diagnosed less than 50 years of age Presence of synchronous, or metachronous colorectal or other LS- associated tumors, regardless of age Colorectal cancer with histology suggestive of MSI-H in a patient less than 60 (tumor infiltrating lymphocytes, Crohn’s like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) Colorectal cancer in a patient with ≥ 2 first or second degree relatives with a Lynch syndrome related cancers regardless of age Hereditary Colon Cancer Predisposition Syndromes • • Sjursen et al  found the sensitivity of the Amsterdam II criteria to be 87% (MLH1), 62% (MSH2), 38% (PMS2), and 48% (MSH6) for identifying individuals with a germline mutation. Hampel et al  also reported that in a population-based study of persons with colon cancer, only three of 23 persons with a germline mutation in an MMR gene met the Amsterdam criteria. Hereditary Colon Cancer Predisposition Syndromes IHC-MMR Tumor Testing Screens the tumor for Lynch syndrome Analyzes presence or absence of 4 proteins MLH1, 95% MSH2, MSH6, PMS2 of individuals with Lynch syndrome will have absence of at least 1 protein on IHC-MMR Absence of staining could indicate a germline mutation At Avera- done on all colon cancer resections and endometrial cancers at time of surgery Hereditary Colon Cancer Predisposition Syndromes Lynch Syndrome Hereditary Colon Cancer Predisposition Syndromes FAP/Attenuated FAP Caused by mutations in the APC gene Classic FAP is associated with 100s-1000s of polyps in the teens-30s The risk for colon cancer for untreated individuals is ~87% by age 45 and 93% by age 50 Attenuated FAP is associated with <100 polyps and older age at onset. The risk for colon cancer is ~70% to age 80 MYH-Associated Polyposis Autosomal Recessive polyposis disorder caused by mutations in the MYH gene 10s-100s of polyps Lifetime risk for colon cancer 43%-100% Hereditary Colon Cancer Predisposition Syndromes Peutz Jeghers Syndrome STK11 gene Breast, Ovarian (often sex cord tumors), pancreatic, and colon cancers Colon polyps and oral freckling (mouth and lips) Juvenile Polyposis Syndrome SMAD4 and BMPR1A genes Juvenile polyps of the colon Colon cancer Hereditary Colon Cancer Predisposition Syndromes Family #1 Col 40 Panc 60 Endo 35 Col 45 Col 40, 50 MSH2 Breast 55 2 Adenomas Col 50 Endo 40 2 adenomas Family #2 Col 80 83 Col 60 PMS2 absent IHC PMS2 mut 2 Adenomas 1 Adenoma Colon 60 Family #3 APC + Colectomy 40 100+ polyps APC + # Colon 45 20 adenomas 22yo 10 polyps 20yo 20 polyps 15yo # No information 12yo Family #4 Dx 70s Dx 80 Dx 57 Dx 60 Dx 75 Dx 54 Dx 70 Dx 45 Normal IHC 25 gene panel = MSH6 VUS Colorectal Endometrial Bladder Dx 71 3 Dx 60 Dx 40 Dx 67 Dx 50 Dx 40s Dx 40s Pancreatic Breast Prostate Variant of Uncertain Significance VUS: A variant of uncertain or unknown significance is a change in the DNA sequence of the gene where it is unknown if it damages the gene or not. DNA Change Classification Deleterious Mutation Positive Result= Damaging change to the gene VUS- Suspected Deleterious Evidence points to most likely damaging/positive Variant of Uncertain/Unknown Significance Unknown if damaging or benign change VUS- Likely Benign Evidence points to most likely negative/benign Benign Polymorphism Negative Result- does not affect gene function Family #4 Dx 70s Dx 80 Dx 57 ATM VUS Dx 60 No Answer Dx 75 Dx 54 Dx 70 Dx 45 Normal IHC 25 gene panel = MSH6 VUS Dx 71 3 Dx 60 Dx 40 Dx 67 Dx 50 Dx 40s Dx 40s ATM VUS- likely benign Colorectal Endometrial Bladder Pancreatic Breast Prostate Hereditary Colon Cancer Predisposition Management: Lynch Syndrome- Depends on the gene involved Colonoscopies 1-2 years starting at age 20-25 or individualized based on family history Consider EGD every 3-5 years starting at age 30-35 (MLH1/MSH2) Prophylactic TAH/BSO when childbearing is complete Consider annual urinalysis starting at age 30-35 Consider annual physical/neurological exam Hereditary Colon Cancer Predisposition Management Classic FAP Annual Colonoscopy starting at age 10-15 Proctocolectomy or Colectomy: Age at surgery depends on polyp load and severity of family history Attenuated FAP Colonoscopy every 1-2 years with consideration of colectomy depending of polyp burden Extracolonic surveillance: Upper Endoscopy starting at age 20-25- earlier if colectomy prior to age 20 Annual Physical exam Annual abdominal exam with consideration of CT or MRI Annual thyroid exam Summary Summary Approximately 5-10% of all cancers are caused by a hereditary gene mutation Family history is an important tool for identifying these families Management guidelines and recurrence risks may differ significantly if a patient has a hereditary cancer syndrome Questions?