The autosomal dominant hereditary cancer syndrome Lynch syndrome (LS; formerly designated hereditary non-polyposis colorectal cancer; HNPCC) arises not only through defects in mismatch repair genes (MLH1, MSH2, MSH6 or PMS2) but also through large 3' deletions of the EPCAM gene. Mutation carriers have 25-70% risk for colorectal cancer, 30-70% risk for endometrial cancer, variable increased risk for ovarian cancer, and increased risks for pancreatic, bladder and breast cancers. The majority of cancer deaths in LS patients are related to non-colorectal, non-endometrial tumors.
Very recent updated National Comprehensive Cancer Network (NCCN) guidelines for colorectal cancer now recommend routine immunohistochemical or microsatellite instability (MSI) testing on all colorectal cancer tumor tissues (an optional strategy is to test tumors in patients < 70 years old). This follows 2013 expert European guidelines (1) summarized below.
European experts recommend that all newly diagnosed colorectal and endometrial carcinomas (or those arising in patients <70 years of age) be tested for loss of mismatch repair function by microsatellite instability or imunohistochemical testing. European experts recommend reflex testing for methylation of the MLH1 promoter gene but do not specify that the indication for such testing is dual loss of MLH1 and PMS2 expression. This strategy of relatively unselected screening is more clinically effective in detecting LS patients and overall more cost effective than identifying candidates by revised Bethesda clinical guidelines. Screening colonoscopy at 3 year intervals effectively decreases mortality in LS patiens, but screening for endometrical cancers is unproven; hence, hysterectomy with bilateral oophorectomy remains a reasonable consideration for some mutation carriers. Screening for gastric, urothelial, prostate and breast cancer remains unproven. Aspirin therapy reduces cancer risk in LS patients, but an optimal prophylactic aspirin dose is unknown.
NCCN guidelines do not require genetic counseling prior to routine laboratory testing of colorectal tumor tissues. With increased diagnosis, there is likely to be increased need for genetic counseling for patients and families with positive test results. Issues of risk to future insurance coverage appear to remain.
In summary, laboratory testing for Lynch syndrome is becoming routine and in some cases may extend beyond microsatellite instability and mismatch repair protein testing to included testing for 3' deletions of the EPCAM gene, methylation of the MLH1 promoter gene and BRAF testing. European experts describe recent evidence that large 3' EPCAM deletions lead to LS but stop short of formally recommending routine EPCAM testing at this time. NCCN guidelines do not address endometrial cancers but European expert recommendations do.
Editorial. Guy E.Nichols MD, PhD