Genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

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Approximately 3% of people who develop colorectal cancer have an autosomal dominant inherited condition known as Lynch syndrome, sometimes referred to as Hereditary Nonpolyposis Colorectal Cancer or HNPCC. Individuals with this condition have a greatly increased chance to develop colorectal and other cancers, especially under age 50. Screening for Lynch syndrome in all patients with newly diagnosed colorectal cancer has been proposed to improve outcomes for patients and/or family members.

EGAPP Recommendation Statement: The EGAPP™ Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.

EGAPP Recommendation (January 2009)

Evidence Report (May 2007)

Supplementary Evidence Report (January 2009)

CDC Summary of EGAPP Recommendation (April 2010)

Translation (July 2012)

Key Questions:

  • Question 1 (Overarching Question): Does risk assessment and HNPCC mutation testing in patients with newly diagnosed CRC lead to improved outcomes for the patient or family members, or is it useful in medical, personal, or public health decision making?

  • Question 2a: Assuming a clinical definition of Lynch syndrome, what proportion of patients has a mismatch repair mutation?

  • Question 2b: Assuming a clinical definition of Lynch syndrome, what proportion of patients has MSI?

  • Question 2c: Assuming a clinical definition of Lynch Syndrome, what proportion of patients has abnormal protein expression by immunohistochemistry (IHC)?

  • Question 2d: How accurate are various predictors, assuming a genetic definition of the Lynch syndrome?

  • Question 3: What are the harms associated with screening high-risk individuals for HNPCC?

  • Question 4: What is known about the analytic (sensitivity, specificity, reproducibility, reliability) and clinical validity of tests that identify HNPCC mutations?

  • Question 5: What are the harms associated with screening for high-risk individuals?

  • Question 6a: What are the management options for CRC patients who are HNPCC positive?

  • Question 6b: Does the identification of HNPCC mutations lead to improved patient outcomes in terms of early detection, mortality/morbidity or management decisions (e.g., counseling, surveillance, treatment, other decision making) by patients and providers?

  • Question 7: What are the harms associated with subsequent management options after identification of HNPCC mutations in CRC patients?

  • Question 8a: What is the efficacy of pre-test genetic counseling for informing family members of potential risks and benefits of testing?

  • Question 8b: What is the accuracy of HNPCC testing in family members in predicting the risk of CRC?

  • Question 8c: Do other factors, such as race/ethnicity, age, gender, or co-morbidities affect the accuracy of the testing?

  • Question 9: What are the harms associated with informing/counseling family members or with subsequent testing for HNPCC mutations?

  • Question 10a: What are the management options for family members of CRC patients who have a positive HNPCC test?

  • Question 10b1: Does the identification of HNPCC mutations lead to improved outcomes in terms of decision making by patients, family members and providers, or public health policy?

  • Question 10b2: Does the identification of HNPCC mutations lead to improved outcomes in terms of early detection and mortality/morbidity of patients, family members?

  • Question 11: What are the harms associated with subsequent actions or interventions for family members?

Why EGAPP Selected this Topic for Review:

Key Criteria: Prevalence and severity of colorectal cancer; availability of effective interventions for patients and family members.

Other Considerations: More established test with a larger published literature, and challenges the EGAPP methodology with regard to assessment of family-related outcomes.