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NCCN's Updated Inherited Colorectal Cancer Risk Guidelines Features Gene-Specific Information

NEW YORK – The National Comprehensive Cancer Network published updated guidelines on Tuesday in which it has attempted to make it easier for oncologists and genetics professionals to understand the cancer risks, surveillance, and prevention strategies for Lynch syndrome based on the genetic mutations a patient has inherited.  

Lynch syndrome is an inherited cancer syndrome that increases the risk for colorectal and other cancers (uterine, stomach, liver, kidney, brain, and certain types of skin cancers) before age 50. The syndrome is caused by inherited mutations in MLH1, MSH2, MSH6, PMS2, and EPCAM, which are genes involved in DNA mismatch repair.  

In the latest version of its guidelines, entitled "Genetic/Familial High-Risk Assessment: Colorectal," the NCCN has streamlined information about cancer risks with each of the five Lynch syndrome-linked genes. Each gene has a dedicated table with estimates of at what age, on average, mutations carriers could present with a dozen associated cancers; the cumulative risk of diagnosis through age 80 for mutation carriers; and, for comparison purposes, the lifetime risk of each cancer in the general population. 

For each gene and associated cancer type, there are also charts discussing the evidence supporting specific surveillance and prevention strategies. For example, for patients with MLH1 mutations, the NCCN tables note there is data showing that daily aspirin use for at least two years may decrease colorectal cancer risk in Lynch syndrome patients, and that studies are ongoing to learn more about this preventive strategy. On the other hand, for patients concerned about MLH1-linked urothelial cancer, the NCCN informs that there is insufficient evidence to recommend a particular surveillance strategy.  

Additionally, the updated guidelines now highlight the use of PCR and next-generation sequencing to determine microsatellite instability, which is another way to determine whether patients' mismatch repair process is hobbled and they have Lynch syndrome. Both testing methods determine whether patients are MSI-high by gauging microsatellite repeats.   

With regard to using NGS to determine MSI status, the NCCN said that "sophisticated bioinformatics protocols" are needed, and depending on the specific bioinformatics program, whole-exome sequencing, whole-genome sequencing, or targeted genomic sequencing data may be used.  

"Tumor mutational burden can be used as a surrogate to some degree for MSI," the NCCN stated in the guideline, "but there are causes of increased TMB other than [mismatch repair deficiency]."  

The FDA in June approved Foundation Medicine's FoundationOne CDx as a test to determine which refractory solid tumor patients have high TMB and may be eligible for pembrolizumab (Merck's Keytruda). The NGS test also reports out patients' MSI-high status. 

The NCCN further recommended that any patient with a tumor that is found to be MSI-high by NGS should be referred to a cancer geneticist for germline mismatch repair testing to assess their inherited or familial risk for cancer.  

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