Differentiating Lynch-Like From Lynch Syndrome

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Lynch syndrome is a hereditary condition found in ~3% of all colorectal cancer patients and is defined by germline inactivation in one of the DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hMSH6, hPMS2) (1,2). One allele is inactivated in every cell in a Lynch syndrome patient most commonly by pathogenic mutation or deletion of hMSH2 or hMLH1, or less commonly by pathogenic mutation of hMSH6 or hPMS2. In some Lynch syndrome patients, germline deletion of the 3’ end of EPCAM (also known as TACSTD1) is found, and this deletion causes allele-specific methylation of hMSH2 that is immediately upstream from EPCAM on chromosome 2, silencing the transcription of hMSH2 (3). Patients with Lynch syndrome can develop synchronous and metachronous cancers at relatively young ages most commonly of the colon, but also of the endometrium and ovaries, the remainder of the gastrointestinal tract, the urinary tract, brain (glioblastomas), and specific skin cancers (Muir-Torre variant). With both the germline DNA MMR allele and the second somatic intra-cancer DNA MMR allele nonfunctional, DNA MMR enzyme activity is abated or lost within Lynch syndrome cancers. This allows multiple mutations to accumulate and advantages the tumor for growth and spread, and allows manifestation and detection of microsatellite instability (MSI) from within tumors that develop (4). Only a portion of Lynch syndrome patients and families might be initially identified by the clinically oriented Amsterdam criteria and/or Bethesda guidelines; most patients may be identified through MSI testing and DNA MMR protein immunohistochemistry (IHC) of the patient's tumor (1). However, germline testing for mutations within the DNA MMR genes is the ultimate the gold standard for characterizing Lynch syndrome families (1,2).