Molecular Pathology of Diagnostic Evaluation in Lynch Syndrome

Research output: Contribution to conferenceAbstract


Lynch Syndrome (LS) is an inherited autosomal dominant disorder predisposing individuals to a range of cancers, most commonly endometrial and
ovarian cancer in the female reproductive tract, and colorectal cancer in the gastrointestinal tract. It is caused by pathogenic mutations of the DNA
mismatch repair (MMR) pathway genes, MLH1, MSH2, MSH6 and PMS2, which prevent the detection and repair of DNA replication errors,
mismatches and insertion/deletion loops, and some other nucleotide abnormalities. Gynaecological cancers may occur as sentinel events for Lynch
syndrome in women. Hence, there is an opportunity to screen for and diagnose LS in women before other cancers occur, permitting cancer
surveillance programmes, preventative measures, cascade testing of at-risk relatives and influencing treatment options, such as immune checkpoint
blockade. Screening of cancer samples for LS usually involves MMR IHC and/or MSI testing, with MLH1 promoter methylation testing to distinguish
sporadic MLH1-negative cancers, with subsequent germline sequencing. MMR IHC analysis can identify the specific protein that is lost or abnormal,
indicating the likely mutated gene. MMR proteins form heterodimers, MLH1 - PMS2 and MSH2 - MSH6, that are stable. However, MMR proteins are
unstable in the unpaired state. Although MLH1 and MSH2 can form stable heterodimers with other proteins, PMS2 and MSH6 only dimerise with MLH1
and MSH2 respectively, affecting interpretation of the patterns of loss or abnormality, with this interpretation best performed by an experienced
pathologist and with high quality MMR IHC staining requiring participation in a NEQAS scheme.
Original languageEnglish
Publication statusPublished - 2 Jul 2019
EventPathological Society - Leeds Pathology 2019 meeting - Leeds
Duration: 2 Jul 20194 Jul 2019


ConferencePathological Society - Leeds Pathology 2019 meeting


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