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

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.