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Lynch Syndrome /

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)


  • Introductions
  • What are your main concerns? What do you hope to learn today?
  • What do you know about colon cancer?

Review Family and Medical HistoryEdit

  • 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 CancerEdit

  • Third leading cause of cancer in men and women
    • 9% of new cancer diagnoses, 11% of all cancer deaths
    • Incidence is over 160,000 new cases of colon and rectal cancer per year
    • About 5-10% of all colorectal cancers are hereditary
      • 3-7% due to Lynch Syndrome / HNPCC
      • 1% due to FAP
    • About 10-30% of colorectal cancers are familial
    • Average diagnosis is age 44
  • Caused by uncontrolled proliferation of cells in colon or rectum
    • Symptoms may include blood in stool, diarrhea, constipation, reflux, 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, not enough fresh foods, processed foods
      • 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
  • Lynch Syndrome Cancers
    • Colon Cancer
    • Endometrial Cancer
  • Lynch Syndrome Cancers
    • Colon Cancer
    • Endometrial Cancer
  • Ovarian Cancer
  • Gastric Cancers
  • Hepatobiliary Cancers
  • Renal Pelvic Cancer
  • Pancreatic Cancer
  • Skin Cancers (Muir Torre)
  • Brain Cancer

Genetic Etiology of Hereditary Colon CancerEdit

  • 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
      • Other more rare genes
      • 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 AssessmentEdit

  • 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 TestingEdit

  • 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
      • Bethesda Revised Guidelines
      • 1. The patient is younger than age 50.
        2. The patient has multiple HNPCC-associated tumors in the colon or in other areas known to be caused by the same mutations, either at the same time or occurring over a period of time.
        3. A patient younger than age 60 has colorectal cancer that has microscopic characteristics that are often indicative of MSI.
        4. A patient has one or more first-degree relatives who had an HNPCC-related tumor at age 50 or younger.
        5. A patient has two or more first- or second-degree relatives who had HNPCC-related tumors at any age.
  • 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 Instabilty $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 (eg 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 OptionsEdit

  • Screening guidelines
    • Colonoscopy
      • Starting at age 25 or 10 years before age of first colorectal cancer diagnosis
      • Repeat annually
      • Surveillance decreases mortality by 65%, decreases CRC by 62%
      • Promotes early detection, improved survival
    • Endometrial and ovarian cancer
      • Transvaginal ultrasound, CA-125 levels starting at age 25 annually or ten years prior to the youngest age of afflicted family member, whichever comes first.
      • Endometrial biopsy annually starting at age 25 or ten years prior to the youngest age of afflicted family member whichever comes first.
    • Stomach
      • If previous family member affected
      • Upper GI endoscopy every 1-2 years starting at age 25 or ten years prior to the youngest age of afflicted family member whichever comes first.
    • Urinary tract
      • If previous family member affected
      • Ultrasound and urine cytology every 1-2 years starting at age 25 or ten years prior to the youngest age of afflicted family member.
      • Annual Examination of Skin for cancerous growths
  • Prophylactic surgery
  • Subtotal colectomy if cancers are discovered
  • Hysterectomy with oophorectomy following child bearing years

  • Chemoprevention
  • Current multicenter trial recruiting patients with known mutation or high MSI tumors and Amsterdam positive family history
  • Current trial occuring in the UK
  • Not known if chemopreventative therapies are effective for those with Lynch syndrome however prophylactic chemotherapy is prescribed at Stage II and above.

Psychosocial IssuesEdit

  • Motivation for undergoing testing
    • Decision-making about testing, surveillance, and prevention
    • Protect lives
    • Stress level, previous experiences with cancer either within self or other family members
    • Protection of family members
    • Hope and enhanced longevity

  • Reactions to positive, negative, and uninformative results
    • Changes in medical management
    • Initial feeling of being overwhelmed
    • Feelings of relief and/or resolution
    • Notification to family members in order to protect them
  • Family, social support system


  • 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
:*Lynch Syndrome International
P.O. Box 5456
Vacaville, California


  • 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).


The information in this outline was last updated in 2002.

'This material has been imported fom the wikibook "Genetic counseling"[ '] under the GNU Free Documentation License.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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