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

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