Although the benefits of universal screening for colorectal cancer (CRC) and endometrial cancer (EC) are well known and supported by widespread consensus among major medical and specialty societies, the benefits of screening for other major cancers associated with Lynch syndrome (LS) remain unclear. Found in approximately one in 279 individuals, LS is caused by a mutation in mismatch repair genes involved in the correction of errors during DNA replication and is associated with an increased lifetime risk of several cancers, including EC and ovarian cancer (OC).
The major cancers linked to LS are colorectal, uterine, ovarian, urinary, and sebaceous tumors (ST). Approximately 5% of urinary tumors (UTs) are thought to be caused by inherited genetic syndromes, whereas 25% of OCs are estimated to be due to an inherited syndrome.
Universal Lynch Syndrome Screening of Various Cancers
For a paper published in Familial Cancer, my colleagues and I aimed to systematically compare the yield of LS screening across various LS-associated cancers, conducting a literature review between 2005 to 2017 to identify studies performing universal screening for LS in unselected EC, OC, and other cancers. We presented the first comparative analysis of universal LS screening of various cancers and extracted data pooled from 56,371 patients across 129 study arms from all over the world.
Our study showed that the pooled yield for universal LS screening in EC was higher than that in CRC (22.65% vs. 11.9%), while the pooled yield for universal LS screening in OC (11.3%) was similar to that in colon cancer. The screening yield was highest in STs (53%), likely due to its inherently rare nature compared with colorectal, uterine, ovarian and urinary tumors, which are associated with strong extrinsic risk factors. The pooled rates of confirmed LS were also highest in STs (19%), followed by EC (2.6%), CRC (1.8%), and OC (0.83%).
We also identified the issue of variation in somatic mutations, which yield positive results during LS screening that are not due to an underlying germline mutation. Somatic mutations occur only in the tumor cells; other cells are not affected since there is no germline mutation. Therefore, those with somatic mutations do not carry risk for other cancers and their families do not require additional screening. Somatic mutations were significantly higher in EC (17%) compared with CRC (5.2%).
LS Screening to Include Ovarian & Uterine Cancers, Plus STs
Highlighting the differences in LS screening and germline positivity in various LS- associated cancers has never before been attempted. This useful comparison for physicians illustrates the risk of LS, not only when they see patients with CRC or UT, but also those with sebaceous, urinary, and ovarian tumors (Figure). The results of this study support expanding universal LS screening to include OC, as well as urinary cancer and STs. We recommend that gynecologists and other physicians obtain a detailed family history of cancer and consider the possibility of LS when multiple family members have any of the major Lynch-associated tumors. In addition, we recommend wider testing for somatic mutations in LS screening positive for EC.
We concur that larger studies will need to be undertaken to confirm these findings, which will have important implications for the future design of LS screening programs. Further studies will also be needed to assess the cost-effectiveness of expanded universal LS testing and its burden on existing genetic counseling services.