Understanding Lynch Syndrome and Associated Cancer Risk: Epidemiology

In this second episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, delves into the epidemiology of Lynch syndrome, the pathogenic variants in the mismatch-repair genes that cause the condition, and criteria utilized to identify it.

Lynch syndrome is the most commonly inherited colon cancer syndrome, and it accounts for approximately 3% of all newly diagnosed cases of colorectal cancer. However, the percent likelihood of identifying Lynch syndrome increases as the age of colon cancer diagnosis decreases. This is particularly relevant now, since the prevalence of early-onset colon cancer—specifically in individuals identified and diagnosed at less than 50 years is increasing in the United States. Lynch syndrome is identified in about 10% [of the] patients [with colon cancer] diagnosed at less than 50 years. In those who are identified at less than 35 years, [the percent likelihood of] Lynch syndrome identification increases to 23%. This has been the rationale for the recommendation to offer germline genetic testing to all patients [with colon cancer] who are diagnosed before the age of 50 years.

Lynch syndrome is an autosomal-dominant condition, and it is caused by pathogenic variants in the mismatch-repair genes MLH1, MSH2, MSH6, PMS2, as well as the gene EPCAM, in which deletions [can] cause epigenetic silencing of MSH2. Because of its autosomal-dominant inheritance, many families have come to the attention of oncologists and gastroenterologists in cancer registries because of their increased burden of colorectal cancer.

Family history of colon cancer, as well as an early diagnosis of colon cancer, served [as] the backbone for the clinical criteria that were originally developed [by Dr Henry Lynch] and were used to identify Lynch syndrome, dating back to the 1960s. However, with the advent of molecular tumor testing, and the detection and discovery of germline alterations associated with Lynch syndrome in the 1990s and early 2000s, improvements have been made beyond the use of the clinical criteria to optimally identify Lynch syndrome.

The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated cancers exhibit its hallmark feature, notably microsatellite instability [MSI]. In these cases, there’s typically loss of immunohistochemical expression of 1 or more of the proteins associated with the mismatch-repair genes. As such, tumor testing is a key component in the diagnosis of Lynch syndrome in addition to family history.

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