Hereditary Syndromes Part 1

Episode Notes

Background/basics of hereditary cancers

1. Hereditary cancer syndromes describe the constellation of increased cancer risks seen in a family or genetically linked group due to pathogenic germline mutations in certain genes

1. Cancers related to hereditary syndromes often have early ages of onset

2. Familial cancers vs. hereditary cancer syndromes: familial cancers not linked to a specific gene; can be influenced by environmental/lifestyle factors, chance clustering of cancers, or genetic variation in low penetrance genes

2. Can have variable inheritance patterns (frequently autosomal dominant)

3. Penetrance: the chance that a person with a genotype (like a BRCA1, RAD51C, or MSH2 mutation) will develop the phenotype (like development of breast, ovarian, or uterine cancer)

1. Higher penetrance = higher chance of developing associated cancers

1. BRCA 1 and 2, Lynch syndrome have high penetrance

2. Moderate penetrance: RAD51C, RAD51D, BRIP1, PALB2 = lower lifetime cancer risk, cancers may develop later

1. Ex: lifetime risk of ovarian cancer with RAD51C is 10-15%, and 3-5% with PALB2

3. Next episode will cover specific cancer risks and decision-making surrounding risk reduction for specific syndromes

4. Variant of unknown significance: germline mutation which is not classified as definitively benign or definitively pathogenic. The majority (up to 90%) eventually get reclassified as benign

1. Providers need to periodically recheck whether the gene has been reclassified; can be done at ClinVar

2. More common in patients of color as they were historically excluded from studies evaluating germline variants

5. Proband = first person in a family diagnosed with cancer, triggering genetic testing

1. Criteria for germline genetic testing

1. Patients with a cancer diagnosis

1. Ovarian cancer: everyone with an ovarian cancer diagnosis should have germline genetic testing

1. Up to 18% of epithelial ovarian cancers are associated with a BRCA ½ mutation, 5-10% more are associated with other pathogenic germline variants

2. Peutz Jegher syndrome is associated with GI cancers, breast cancers, rare non-epithelial ovarian cancers, and gastric-type cervical adenocarcinoma.

1. If somatic STK11 mutation found > germline testing should be done

2. Other clinical criteria for testing are not based on gyn cancer history

3. Li fraumeni: p53 mutation. No specific guideline for testing for Li-fraumeni for gyn indications, but there have been observed increases in ovarian cancer in Li-Fraumeni patients. All patients with ovarian cancer should get germline testing. 

2. Endometrial cancer

1. Lynch: Bethesda guidelines (revised) originally designed for patients with colorectal cancer, to inform who should get genetic testing. Have largely been replaced by reflex tumor testing (recommended for all endometrial cancers)

1. Options for evaluating for Lynch syndrome

1. Assessment of MMR first: IHC for MLH1, MSH2, MSH6, PMS2 (test for missing protein expression)

1. MLH1 or PMS2 mutation: promoter hypermethylation testing

1. Promoter hypermethylation is an epigenetic change altering protein expression and is NOT associated with Lynch

2. If no hypermethylation or if a mutation in the other Lynch genes > germline genetic testing

3. If unable to test for methylation at your institution, then all patients with MMRd on IHC should be sent for germline genetic testing

2. Alternate strategy: test for MSI first > test for hypermethylation in MLH1 and PMS2 if the tumor is MSIH >genetic counseling/testing if no hypermethylation

3. Alternate strategy: germline testing for all

2. Roughly half of patients with MMRd without hypermethylation will ultimately have Lynch

2. NCCN guidelines now include a recommendation to “consider” germline genetic testing for all patients with endometrial cancer

1. Pros: Higher chance of identifying people with Lynch and other non-pathogenic variants (up to 14% of endometrial cancers 

2. Cons: To qualify for use of immunotherapy in endometrial cancer, would still need to test for MMR or MSI; pathogenic variants may not have treatment implications; risk of revealing unexpected results; increased detection of VUS; challenges to infrastructure –lack of sufficient access to genetic counseling and appropriate cascade testing

3. Cowden syndrome: PTEN germline mutation

1. Increased risk of breast, endometrial, colon, thyroid cancer, benign neoplasms

2. Testing should be done if patients meet three or more major criteria or two or more major criteria + three or more minor criteria

1. Endometrial cancer, breast and thyroid cancer count as major criteria

2. Full testing criteria available here

2. Patients without a cancer diagnosis –choosing who to test 

1. Testing patients <18 yo is not generally recommended as it would not impact medical management

2. Cascade genetic testing: family members of a proband are contacted and recommended for testing

1. Feasible and effective

2. Most common/employed strategy

3. Specific algorithms for which family members need genetic testing depend on the syndrome identified in the proband

1. Ideally the proband is tested first

2. Family history of ovarian cancer (first or second degree blood relative at any age, or a probability of a pathogenic variant >5% based on probability models like Tyrer-Cuzick, BRCAPro, CanRisk) > genetic counselign and consideration of genetic testing

1. Multigene panel to include: ATM, BRCA1, BRCA2, BRIP1, MMR (MLH1, MSH2, MSH6, PMS2, EPCAM), PALB2, RAD51C, RAD51D

3. Family history of Lynch: a family history of 1 or more first-degree relatives with a CRC or EC diagnosed before age 50; one or more first degree relatives with a CRC or EC and a synchronous or metachronous lynch-syndrome-associated cancer, regardless of age; two or more first or second degree relatives with LS-related cancers with at least one diagnosed before age fifty, or three or more first or second degree relatives with LS-related cancers regardless of age of diagnosis. 

1. Amsterdam II criteria: criteria for which families/patients should be managed as if they have Lynch, in the absence of available genetic testing

3. Previous genetic testing with a limited panel: recommend repeating if updated testing panels are available

4. Member of a population with a higher risk of germline genetic mutations (eg: Ashkenazi Jewish descent)

5. Population based testing: all persons tested for higher penetrance genetic mutations, regardless of family history

1. Has not been traditionally employed due to cost effectiveness and low yield; may become more accessible in the future

6. Traceback testing: genetic testing performed on tumor registry specimens from deceased cancer patients > information provided to family members. Not used clinically due to ethical implications; is under research.

2. Considerations for germline testing

1. Testing quality: use a lab certified by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA).

1. If original testing was done at a non approved lab (including direct to consumer commercial labs, which often used microarray-based SNP testing and are not validated for clinical use), needs to be repeated.

2. Confirm which genes will be included

2. Counseling prior to testing:

1. Can be done by a clinician or genetic counselor. Ideally genetic counselors should be integrated into clinical care teams. If not available at your institution, can find telehealth genetic counselors at Find a Genetic Counselor - NSGC

2. Review:

1. What information patients may gain

1. May have a specific gene in mind; may identify this mutation

2. Possibility of unexpected results: mutation in a gene we weren’t expecting

3. True negative results

4. Uninformative negative results and VUS

1. Uninformative negative: negative result in the setting of other family members with cancer with negative results or without genetic testing. Can’t determine whether the negative result is protective for our patient.

2. Review implications of a positive result

1. Availability/lack of availability of preventative and screening options

3. Recommendations for cascade testing after results are available: encourage patients to notify their family members or to give consent for family members to be notified

4. Legal implications

1. 2008 Genetic Information Nondiscrimination Act (GINA): prevents insurance companies and employers from discriminating based on genetic information

1. Life insurance companies are still able to take genetic testing results into account

3. Counseling after testing

1. Pathogenic or likely pathogenic germline mutation: 

1. Confirm access to a genetic counselor 

2. Discuss medical risks

1. Best practices are to convey risks as estimates; convey the lifetime risk, as well as when that risk starts to increase

3. Discuss options for prevention and screening

4. Emphasize the importance of ongoing screening: adherence to screening decreases overtime

5. If applicable, discuss fertility planning, including options for IVF and preimplantation genetic testing (PGT) or embryos

1. Refer to oncofertility or fertility specialist if applicable

6. Refer to appropriate oncology clinics if additional risks beyond gynecologic cancers

7. Re-discuss disclosure to family members

8. Refer for supportive services as needed

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