Lynch Syndrome (LS)

Colorectal cancer (CRC) is a major public health problem, being the third most common cancer in men and women.7It is the second and third commonest cause of cancer related deaths in men and women respectively and is largely preventable with recommended population screening.7,8It is estimated that approximately 3% of CRCs are attributable to LS.9-11This autosomal dominant genetic disorder is associated with greatly increased risks of developing colorectal, endometrial, gastric and other cancers.9-12Despite the increased risk of cancers seen in LS patients, long-term follow-up studies show that compliance with current surveillance recommendations is highly successful. LS patients show no increase in cancer-related mortality when compared to mutation-negative family members on long-term follow up.13Unfortunately, unless there is strong clinical suspicion, many cases of LS are missed.12Furthermore, standard population CRC screening guidelines fail to provide early detection or prevention for most LS colon cancers as they tend to occur at young ages.9-12There is hence a clear need for better ways to detect patients at risk of LS.

The challenge in diagnosing LS, in contrast to Familial Adenomatous Polyposis, is that it does not have pathognomonic clinical features of polyposis that distinguish it from a sporadic cancer. Guidelines for LS testing comprise one for screening of resected tumour specimens and another that targets germline genetic testing (usually blood) of at-risk individuals. Germline genetic testing by sequencing with or without multiplex ligation-dependent probe amplification is cost-effective in individuals who are of sufficient risk.14

Unfortunately, a high proportion of patients are missed when clinicians rely only on high risk clinical and/or pathological features.10, 15 Indeed, the revised Bethesda guidelines are now known to be inadequate for LS screening when family cancer history is not available. A universal screening paradigm greatly increased the rate of LS detection16, and the approach of universal screening for mismatch repair defect (MMR), the hallmark feature in LS9, 15, in all colorectal cancer specimens, with either tumour microsatellite instability (MSI) testing with or without BRAF testing, or immunohistochemistry (IHC) staining of MMR proteins, has been proposed.17For screening, IHC is thought to be almost equally sensitive as MSI but more readily available.15Either MSI and/or MMR IHC as a screening tool to identify candidate LS cases for further workup are available in both tertiary cancer centres (NCIS and NCCS). However, while universal screening has been shown to be cost-effective18-21, infrastructure comprising trained medical staff, pathologists and workflows is required for effective implementation.22-24As such, there is disagreement within the workgroup with regard to universal screening, with 4 of 5 members voting not to include it in the current SCAN guidelines, given the lack of clear data and untested assumption in cost-effectiveness analysis studies that multiple family members will be tested following the identification of gene mutation in the proband in the local context.

The guidelines for LS were divided into criteria for tumour screening for MSI or IHC for MMR proteins, and criteria for referral for germline genetic testing. The 2013 American College of Medical Genetics (ACMG) guidelines25and the 2014 NCCN guidelines were adopted as the backbone guidelinesfor tumour screening and germline genetic testing respectively. Tumour screening guidelines were largely based on the revised Bethesda criteria 26, and were included as there are specialists who have access to tumour screening and sufficient expertise to interpret results in at-risk individuals. However, the workgroup acknowledged that not all physicians are willing or able to order tumour screening tests, and added a special note that physicians may refer patients who fulfill criteria for tumour screening to a cancer genetics clinic for further work-up, rather than arrange tumour testing themselves.