# 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.