What are the guidelines for testing in familial risk-rectal cancer?

Updated: Apr 06, 2021
  • Author: Burt Cagir, MD, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Screening for Familial Risk

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Guidelines for Lynch syndrome screening have been developed by the National Cancer Institute (Bethesda guidelines) and the NCCN. [33]

The American Gastroenterological Association recommends testing all patients with colorectal cancer for Lynch syndrome; the tumor should be tested for MSI or with immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins. [92]

The European Society for Medical Oncology (ESMO) guidelines for familial risk-colorectal cancer  [93] , which have been endorsed by the American Society of Clinical Oncology (ASCO) [94]  includes the following recommendations:

  • Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all patients with colorectal cancer. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines
  • If loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be conducted to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.

  • If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).

  • Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis.

The American College of Gastroenterology recommendations are in general agreement with ESMO. [95]

Revised Bethesda guidelines for Lynch syndrome and microsatellite instability

Because cancers with MSI account for approximately 15% of all colorectal cancers, in 1996 the National Cancer Institute developed the Bethesda guidelines for the identification of individuals with HNPCC who should be tested for MSI. These guidelines were most recently revised in 2002. [96]

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