Diagnostic Strategies for Early Lynch Syndrome Detection: From Molecular Testing to Economic Evaluation

Abstract

Lynch syndrome (LS) is an autosomal dominant inherited syndrome that predisposes to multiple malignancies, in particular colorectal cancer (CRC) and endometrial cancer (EC). The lifetime risk of developing CRC for a LS mutation carrier is 25 to 70%, while women with LS carry a lifetime risk to develop EC of 13 to 65%, dependant on family history and the affected MMR gene In addition, LS carriers have an increased risk of up to 15% to develop other malignancies. These in particular include gastric, skin, ovarian and small bowel, as well as urinary tract cancers. LS is caused by germline mutations in the mismatch repair (MMR) genes or deletion of the 3’ region of the TACSTD1 gene. In addition, LS can be caused rarely by germline hypermethylation of the promoter regions of the MLH1 or MSH2 gene. Recognition of LS is of utmost importance in order to provide adequate counseling and targeted surveillance to individuals at risk. Colonoscopic surveillance has been proven to reduce CRC morbidity and mortality by 65-70%.18-20 Furthermore, surveillance for EC by transvaginal ultrasound and tumormarker analysis may enable detection of premalignant lesions or EC at an early stage, however this requires further proof. Alternatively, prophylactic hysterectomy and bilateral salpingo-oophorectomy are offered to female LS mutation carriers when childbearing is complete. Since molecular and genetic testing is available for the identification of LS, dedicated treatment and surveillance can be offered to LS mutation carriers and their relatives who do carry a mutation. On the other hand, non-carriers can be relieved from the anxiety involved with the syndrome and burdensome surveillance programs.