Handbook of Genetic Counseling/Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Contracting Introductions What are your main concerns? What do you hope to learn today? What do you know about colon cancer? Review Family and Medical History Medical History How have you gotten to this point? Screening practices? Other significant illnesses, hospitalizations? Family History Other individuals with any type of cancer? If affected: Age and date at diagnosis, death Current age Type, location, stage of primary cancer Secondary cancer - metastasis or new primary Environmental exposures If unaffected: Current age Health and history of illness If deceased, cause and age at death Screening practices Family thoughts on cause of cancer? Colon Cancer Third leading cause of cancer in men and women 9% of new cancer diagnoses, 11% of all cancer deaths Incidence is over 130,000 new cases per year About 5-10% of all colorectal cancers are hereditary 3-5% due to HNPCC 1% due to FAP About 10-30% of colorectal cancers are familial Caused by uncontrolled proliferation of cells in colon or rectum Symptoms may include blood in stool, diarrhea, constipation, stomach cramps, frequent bloating, weight loss, or unusual and continuing lack of energy Cancer cells may enter blood or lymphatic system and metastasize to form secondary tumors in other parts of body Multifactorial disorder involving both genetic and non-genetic factors Non-genetic factors Diet: high fat, low fiber, high red meat intake Colorectal polyps (adenomatous polyps) Alcohol, cigarettes Chronic disease of bowel (Crohn's disease, inflammatory bowel disease, ulcerative colitis) Obesity Genetic factors Hereditary colorectal cancer syndromes HNPCC and FAP Rare colorectal syndromes: Peutz-Jeghers Syndrome, Juvenile Polyposis Coli All cancers have genetic component but not all are hereditary Genetic Etiology of Hereditary Colon Cancer Autosomal dominant inheritance Each child of mutation carrier has 50% chance of inheriting mutation Mutations in DNA mismatch repair genes MSH2 at 2p22 MLH1 at 3p21 PMS1 at 2q31 PMS2 at 7p22 MSH6 at 2p16 60% of HNPCC due to mutations in MSH2 or MLH1 Carcinogenesis due to loss of heterozygosity of one of genes above Causes defective mismatch repair Mutations accumulate throughout the genome Microsatellite instability (MSI) Provides indirect evidence for presence or absence of germline mutation Due to genome wide instability of replication and repair of repeat sequences 10-15% of sporadic tumors show MSI, >95% of HNPCC tumors show MSI Penetrance variable - use lifetime cancer risks for mutation carriers Mutation also increases risk for other types of cancer besides colorectal cancer 30% risk of second primary 10 years after original diagnosis 50% risk of second primary 15 years after original diagnosis +Lifetime Risks for HNPCC-Related Cancers Site Population Risk Hereditary Risk Colon/Rectum 5% 70-80% Endometrium 1.5% 60% Ovarian 2% 9% Urinary Tract (Kidney and Ureter) <1% 10% Stomach <1% 19% Small Intestine <1% <5% Cancer Risk Assessment Features of hereditary colorectal cancer More than one generation affected Early age at diagnosis Bilateral or multiple primary cancers Combination of tumors consistent with specific cancer syndrome Strengths and limitations of cancer risk assessment Knowledge of family history may be limited Cancer occurs with or without hereditary cancer syndrome Can't diagnose on the basis of family history information alone Features associated with HNPCC Polyps present in small numbers or not at all Proximal (right-sided) colon cancer Mean age at diagnosis is 45 years Individual risk based on personal/family history: ________ Muir-Torre Syndrome Variant of HNPCC Associated with MSH2 or MLH1 mutations Typical features of HNPCC Also includes sebaceous gland tumors and keratoacanthomas Turcot Syndrome Rare hereditary syndrome of multiple colorectal adenomas and brain tumors Two subtypes APC mutations associated with medulloblastomas MMR mutations associated with glioblastomas Genetic Testing Diagnostic/Testing Criteria for HNPCC Amsterdam Criteria Family must meet ALL of the following Three cases of colorectal cancer One affected person is first-degree relative of other two Two successive generations affected One diagnosis < 40 years FAP excluded in cases of colon cancer Tumors verified by pathology Failure to meet these criteria DOES NOT exclude HNPCC Modified Amsterdam Criteria Family must meet ALL of the following Three relatives with HNPCC-related cancer One person is first-degree relative of other two Two successive generations affected One diagnosis < 50 years FAP excluded in cases of colon cancer Tumors verified by pathology HNPCC-related cancers include colorectal, endometrial, small bowel, ureter, renal pelvis) Bethesda Guidelines for eligibility for MSI testing Family or proband meets at least one criteria Family fits either Amsterdam criteria Proband has two HNPCC-related cancers Proband has CRC plus 1st degree relative with HNPCC-related cancer or CRC adenoma <45 years Colorectal or endometrial cancer diagnosed before 45 years Right-sided colon cancer if undifferentiated diagnosed before 45 years Signet-ring cell type colorectal diagnosed before 45 years Colon adenomas diagnosed before 45 years If high MSI, proceed to germline mutation testing Common adult cancers may be due to one of several genes or genetic and environmental interactions Negative result difficult to interpret since it can be more than one gene Preferable to identify mutation in relative with cancer before testing other at-risk relatives General population screening not appropriate for this reason DNA banking is option to defer testing until sometime in future Testing procedures Process Blood drawn here and sent to outside lab (Myriad) Results usually take about 4 weeks Payment methods Patient pay with check, money order, credit card Insurance claims Submit patient insurance authorization with sample Requires 20% copay or insurance verified patient portion Medicare claims - Medicare Waiver of Liability required Institutional pay - Myriad bills institution directly Current prices Comprehensive COLARIS (MLH1 and MSH2 sequencing) $1950 Single Site COLARIS (known family mutation) $315 Micorsatellite Instability $600 Used to screen before DNA testing Must be done on tumor tissue Cannot be billed to insurance Practice guidelines for testing If positive for Bethesda criteria, start with MSI If MSI high, consider genetic testing If MSI low or negative, consider testing if Amsterdam positive If Bethesda and Amsterdam negative, manage based on family history Mutation identified Increased risk for cancer Gene could be passed on to children Other at-risk relatives should be informed and offered counseling Important to establish management plan Insurance issues Mutation not identified Inherited cancer can't be ruled out since mutation may have been missed or exist in another gene May be no genetic explanation for cancer in family Person with cancer who does not have mutation may be sporadic case Relatives may still be at risk and should discuss family history with their doctor Limitations of testing Can't predict when a person with a mutation will develop cancer Not all persons with mutation will develop cancer Some mutations may be missed or can't be interpreted Efficacy of screening for some related cancers (e.g. ovarian) is unknown Benefits of testing May provide information Explanation for cancer in family Increased surveillance or plan for future Clarify risks to children and other family members Reassurance Colon surveillance in at risk persons proven to reduce mortality Risks of testing Insurability Employment issues Confidentiality May alter family relationships Adverse psychological effects Survivor guilt Transmitter guilt Depression Anxiety Not appropriate to offer testing for adult onset disorders for prenatal diagnosis or to anyone under age 18 Screening and Management Options Screening guidelines Colonoscopy Starting at age 25 or 5-10 years before age of first colorectal cancer diagnosis Repeat every 1-2 years Surveillance decreases mortality by 65%, decreases CRC by 62% Promotes early detection, improved survival Endometrial and ovarian cancer Transvaginal ultrasound, CA-125 levels starting 30-35 every 1-2 years Endometiral biopsy annually starting at age 25 Stomach If previous family member affected Upper GI endoscopy every 1-2 years starting at age 30 Urinary tract If previous family member affected Ultrasound and urine cytology every 1-2 years starting at age 30 Prophylactic surgery Effectiveness unknown so no recommendations for or against surgery Does not eliminate cancer risk Subtotal colectomy Hyterectomy with or without oophorectomy Chemoprevention Current multicenter trial recruiting patients with known mutation or high MSI tumors and Amsterdam positive family history No chemopreventive therapies for HNPCC. NSAIDs can reduce number of adenomas in FAP and may work for HNPCC too Psychosocial Issues Motivation for undergoing testing Decision-making about testing, surveillance, and prevention Stress level, previous experiences with cancer Reactions to positive, negative, and uninformative results Changes in medical management Who else will be told about results Family, social support system Resources IMPACC (Intestinal Multiple Polyposis and Colorectal Cancer PO Box 11 Conyngham, PA 18219 (717) 788-1818 American Cancer Society National Headquarters 1599 Clifton Road, N.E. Atlanta, GA 30329 (800) ACS-2345 Hereditary Colorectal Cancer Registry The Johns Hopkins Hospital 550 North Broadway, Suite 108 Baltimore, MD 21205-2011 (410) 955-3875 References Everett, J. "Hereditary Non-Polyposis Colorectal Cancer." Genetic Counseling and Cancer lecture (2002). "Identifying and Managing Risk for Hereditary Nonpolyposis Colorectal Cancer and Endometrial Cancer (HNPCC)." American Medical Association (2001). "Module 6: Hereditary Colorectal Cancer Syndromes." OncoSep 43-55. "The Johns Hopkins Guide for Patients and Families: Hereditary Nonpolyposis Colorectal Cancer." The Johns Hopkins University (1995). Notes The information in this outline was last updated in 2002.