Abstract
The report by Aldred Scott Warthin in 1913 of a cancer family history and expanded on by Henry T. Lynch demonstrated one of the most enduring traits observed in patients with Lynch syndrome. The recognition of a variety of malignancies occurring at differing ages within a single family suggested the role of genetic variance on disease expression in an autosomal dominantly inherited genetic condition. With the identification of the genetic basis of Lynch syndrome and the subsequent collection of families and their medical records it has become possible to identify subtle genetic effects that influence the age at which disease onset occurs in this cancer predisposition. Knowledge about genetic modifiers influencing disease expression has the potential to be used to personalise prophylactic screening measures to maximise the benefits for family members and their carers.
Highlights
The primary function of mismatch repair (MMR) genes is to eliminate base–base mismatches and insertion-deletion loops which arise as a consequence of DNA polymerase slippage during DNA replication [1]
Initial studies focused on genes associated with xenobiotic metabolism which have been followed by genes involved in the immune response, DNA repair, cell cycle control and as yet undefined genomic regions identified as a result of large genome wide association studies searching for genetic risk factors for colorectal cancer
The removal of many carcinogens is controlled by a complex process involving phase I enzymes such as cytochrome P450 (CYP), and phase II enzymes that include the glutathione-S-transferases (GSTs) and N-acetyl transferases (NATs) [20]
Summary
The primary function of mismatch repair (MMR) genes is to eliminate base–base mismatches and insertion-deletion loops which arise as a consequence of DNA polymerase slippage during DNA replication [1]. DNA MMR is a housekeeping function of all nucleated cells and as such any breakdown in the fidelity of this process is likely to result in disease irrespective of which gene is affected. Mutations in DNA MMR genes result in a ‘‘mutator phenotype’’ thereby predisposing individuals to a significantly increased risk of malignancy. It has been obvious from the first MSH2 and MLH1 mutation reports that differences in the ages of cancer diagnosis in patients harbouring germline mutations in DNA MMR genes do occur both within and between families. Talseth-Palmer et al. The differences in disease expression both within and between families harbouring the same mutation are most likely a result of environmental, genetic or a mixture of both influences. To the authors knowledge no such study has been undertaken to date and only genetic modifiers have been identified in LS at this time
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
