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***Promotes early detection, improved survival |
***Promotes early detection, improved survival |
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**Endometrial and ovarian cancer |
**Endometrial and ovarian cancer |
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− | ***Transvaginal ultrasound, CA-125 levels starting |
+ | ***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. |
***Endometrial biopsy annually starting at age 25 or ten years prior to the youngest age of afflicted family member whichever comes first. |
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**Stomach |
**Stomach |
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− | + | *Chemoprevention |
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− | + | *Current multicenter trial recruiting patients with known mutation or high MSI tumors and Amsterdam positive family history |
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− | + | *Current trial occuring in the UK |
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− | + | *Not known if chemopreventative therapies are effective for those with Lynch syndrome however prophylactic chemotherapy is prescribed at Stage II and above. |
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− | ** |
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==Psychosocial Issues== |
==Psychosocial Issues== |
Revision as of 19:52, 28 August 2010
Assessment |
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Clinical: Approaches · Group therapy · Techniques · Types of problem · Areas of specialism · Taxonomies · Therapeutic issues · Modes of delivery · Model translation project · Personal experiences ·
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 160,000 new cases of colon and rectal cancer per year
- About 5-10% of all colorectal cancers are hereditary
- 3-7% due to HNPCC/Lynch Syndrome
- 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
- Hereditary colorectal cancer syndromes
- Non-genetic factors
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
- 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
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
- Family must meet ALL of the following
- 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)
- Family must meet ALL of the following
- 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.
- Family or proband meets at least one criteria
- Amsterdam Criteria
- 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
- Process
- 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
- May provide information
- 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 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
- Colonoscopy
- 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 Issues
- 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
Resources
- 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
- 707-689-5089
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.
This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.
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