1st August, 2018, Dr Chee L Khoo
Although one third of patients with colorectal cancer (CRC) have a family history of cancer, only 5% of all patients with CRC have an identifiable cause to their cancer predisposition. Most of these identifiable predispositions are inherited mutations in genes that regulate growth processes in colonic stem cells and/or genome caretakers which ensure the only good clean DNA is passed on to the next generation. The most common of these inherited CRC syndromes is Lynch syndrome.
Lynch syndrome is one of many syndromes under the umbrella group of familial CRCs with germline mutations, hereditary non-polyposis colorectal cancer (HNPPCC). All familial CRC used to be lumped under Lynch Syndrome but with the development of biomarker assays, we are now able to separate out Lynch syndromes with other (almost) similar familiar CRC. The response to chemotherapy is vastly different whether it’s Lynch syndrome or not. To understand those assays, we need to briefly describe the mutations.
The DNA mismatch repair (MMR) system detects post DNA mistakes, so called microsatellites. It synthesise MMR proteins (e.g. MSH2-MSH6 and MSH2-MSH3) which can either excised the mistakes and resynthesise the DNA or commit the cell to death if repair is unsuccessful. Screening of CRC tumours for microsatellite instability (MSI) and expression of DNA MMR genes is an effective strategy to facilitate identification of patients at risk for Lynch syndrome. A subgroup of patients may have intact DNA MMR genes but have defective MMR proteins. They mimic many of the clinical features of Lynch syndrome but without the germline mutations of the DNA MMR genes.
Lynch syndrome can be identified in only 2%-3% of all CRC patients, and approximately 2% of all endometrial cancer patients, the two most common cancers observed with this syndrome. Lifetime risk for CRC is 40-80% and lifetime risk for endometrial cancer in women approaches 50%[2,5]. The incidence of adenomas is not high but those that do arise have a high risk of rapidly progressing to malignancy due to loss of the remaining wild type allele of the mutated mismatch repair gene. Patients can develop synchronous and metachronous cancers at relatively young ages, and Lynch-associated CRCs demonstrate accelerated neoplastic progression, with reports of cancers developing within 3 years after colonoscopy[46]. While CRCs are the most common tumours, risks for malignancies of the endometrium and ovaries, gastrointestinal tract (stomach and small intestine, pancreas, biliary tract), urinary tract, brain (glioblastomas), and skin (keratoacanthomas and sebaceous adenomas) are also increased.
Lynch-like syndrome may account for as many as 60%-70% of cases in which Lynch syndrome is clinically suspected but genetic testing fails to identify a germline MMR gene mutation[4]. Patients with Lynch-like syndrome resemble those with Lynch syndrome in that their tumours manifest MSI and immunohistochemical absence of a DNA MMR protein. Patients with Lynch-like syndrome present with cancer at younger ages, similar to Lynch syndrome (53.7 years vs 48.5 years of age.
CRCs with defective DNA MMR are more likely to be located in the colon proximal to the splenic flexure, often exhibit poor differentiation and mucinous features and demonstrate better survival compared to same-staged patients without MSI CRCs[1-3,33-37]. Intact DNA MMR can recognise chemotherapy-induced nucleotide alterations that trigger cell demise. Loss of DNA MMR function renders the CRC resistant to 5-FU, and 5-FU treatment does not improve survival of patients with MSI CRCs.
Most new colon cancers are now tested for MSI. Family history-based clinical criteria, such as the Amsterdam criteria and/or Bethesda guidelines, have limited sensitivity and identify only a portion of MMR mutation. It does gives us some clinical suspicion to consider Lynch syndrome.
HNPCC encompasses a spectrum of conditions that have significant phenotypic overlap, and making a genetic diagnosis in familial CRC cases can be clinically challenging. They may make up a small proportion of patients with CRC but, even in the absence of an informative genetic test result, clinical suspicion should remain high, and specialised surveillance is justified for at-risk individuals from families affected with HNPCC.
Reference:
John M Carethers, Elena M Stoffel. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer. World J Gastroenterol 2015 August 21; 21(31): 9253-9261
https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer/Lynch_syndrome