Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

Keywords: Constitutional mismatch repair deficiency syndrome; DNA mismatch repair; Familial colorectal cancer; Familial colorectal cancer type X; Hereditary colorectal cancer; Hereditary non-polyposis colorectal cancer; Lynch syndrome; Lynch-like syndrome; Microsatellite instability.

Figure 1

Hereditary non-polyposis colorectal cancer conditions can be dichotomized via microsatellite instability testing and/or DNA mismatch repair protein immunohistochemistry. When MSI [or loss of mismatch repair (MMR) protein expression] is present in the colorectal cancer indicating loss of functional DNA MMR, Lynch syndrome and Lynch-like syndrome remain in the differential. Germline testing for DNA MMR gene mutation can differentiate these two syndromes. When MSI is absent meaning DNA MMR remains intact and functional, consideration for polymerase proofreading associated polyposis and familial colorectal cancer type X should be undertaken. Performing germline testing for POLE and POLD1 mutations might help differentiate these two syndromes. HNPCC: Hereditary non-polyposis colorectal cancer; MSI: Microsatellite instability; CRC: Colorectal cancer.

Figure 2

Loss of DNA mismatch repair forces polymerase slippage mistakes to become permanent frameshift mutations at microsatellite sequences. Depicted is a mononucleotide microsatellite of 10 adenines. During DNA replication, occasional polymerase mistakes allow slippage at microsatellite sequences, creating a heteroduplex structure often with one nucleotide as a loop. With intact DNA mismatch repair (MMR), the deletion loop is recognized, excised, and resynthesized correctly such that daughter cells will maintain fidelity of the proper microsatellite length. In the absence of DNA MMR, the deletion loop becomes a permanent frameshift in daughter cells. Frameshift mutations can occur in non-coding as well as in coding microsatellites; coding frameshifts cause the transcription and ultimate translation of truncated proteins that can act as neoantigens to the immune system.