Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.
“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.
Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.
To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.
After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).
Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.
The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.
SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.