Application of molecular diagnostics for the detection of Lynch syndrome

Abstract

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2–5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15–70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.

Keywords::

• genetic testing
• immunohistochemistry
• Lynch syndrome
• microsatellite instability
• mismatch repair genes

Financial & competing interests disclosure

Maria S Pino was supported by the MGH ECOR Fund for Medical Discovery; Daniel C Chung was supported in part by National Institutes of Health CA92594 and P50 CA127003 and also the Kate J and Dorothy L Clapp Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

^†Syndrome-associated tumors include colorectal, endometrial, ovarian, stomach, small bowel, ureter or renal pelvis, biliary tract, pancreas, brain and sebaceous gland.

^‡Presence of tumor infiltrating lymphocytes, Crohn’s disease-like lymphocytic reaction, mucinous/signet-ring differentiation or medullary growth pattern. Data from [21,22,28].