Understanding Lynch Syndrome and Associated Cancer Risk: Implications of Genotype on Cancer Risk

In this fourth episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, explains the implications of Lynch syndrome genotype on risk of colorectal cancer.

It’s important to consider the implications of the Lynch syndrome genotype because gene-specific considerations for screening are related to the associated CRC risks by genotype. Among the Lynch syndrome genes, MLH1 and MSH2 genes, which were originally thought to be most common, have now been deemed to be less common than MSH6 and PMS2 pathogenic variants. The prevalence of MSH6 and PMS2 has increased now, with the improved DNA mutational analysis and universal tumor screening of all colon cancers. In fact, PMS2 variants are quite commonly detected in extracolonic cancers.

The colon cancer incidence varies by genotype and has been consistently shown in multiple cohort studies. At present, it’s estimated that MLH1 and MSH2 lifetime CRC risk is between 35% and 60%, while MSH6 is 10% to 20% and PMS2 is on the order of 3% to 10%. These cancer risks dictate colon cancer screening recommendations. It has been well established from controlled screening trials that intensive colonoscopy reduces the incidence of colon cancer as well as colon cancer–specific mortality in individuals from Lynch syndrome families.

Because of the variability, however, in gene-specific colon cancer risks, experts in the field have proposed gene-specific screening and surveillance recommendations and this has also been supported by cost effectiveness studies. [As such], most organizations now tailor surveillance recommendations based on the specific gene and a more aggressive screening schedule may be considered on an individual basis; sometimes, [though, it is] being guided by family history.

Our present guidelines for MLH1 and MSH2 support colonoscopy initiation in [those] aged 20 to 25 years and to be repeated every 1 to 2 years. For MSH6 and PMS2, colonoscopy…is recommended at age 30 to 35 years [and to be repeated] every 1 to 3 years. There are additional cancers associated with Lynch syndrome, including cancers of the stomach, small intestine, transitional cell carcinoma of the uterus, ureters and renal pelvis, the pancreas and brain, as well as sebaceous adenomas of the skin. Screening is often individualized and directed [based on] family cancer history.

Check back next Wednesday for the next episode in this series.