Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide.1 Approximately 3% to 5% of colorectal cancers are attributable to a hereditary cancer predisposition related to DNA mismatch repair (MMR) deficiency.2 Deficient MMR (dMMR) results in an inability to correct DNA replication errors and therefore results in an increased risk of cancer.
Individuals with LS have hereditary (germline) defects in one of their genes that encode for an MMR protein. This predisposes them to colorectal and other types of cancer. LS is the most common familial CRC syndrome.3
The gold standard for detection of a germline mutation in MMR genes (MMR deficiency) is germline genetic testing by sequencing and deletion-duplication analysis. However, as mutations in one of four MMR genes can underlie LS, and because of the time-consuming nature and considerable economic burden associated with sequencing all four MMR genes, the decision to offer germline genetic testing to diagnose LS is commonly made in a stepwise manner.4 Patients may be pre-screened for potential hereditary CRC based on age or family history,5,6 followed by testing of tumour samples for signs of dMMR, and ultimately germline genetic testing.
To assist decision-makers considering the implementation of dMMR tumour testing, CADTH conducted a health technology assessment (HTA) on the clinical utility, diagnostic accuracy, cost-effectiveness, and related patient perspectives and experiences of dMMR testing strategies. The ability of dMMR tumour test results to inform CRC prognosis or chemotherapy response was also evaluated.
The Health Technology Expert Review Panel (HTERP) recommends universal dMMR tumour testing for patients with colorectal cancer, followed by reflex tumour testing for MLH1 promoter hypermethylation.
Technology
While germline genetic sequencing is considered the gold standard to find an MMR gene mutation, the presence of functional tumour MMR deficiency can be assessed by either tumour microsatellite instability (MSI) testing using polymerase chain reaction (PCR) to detect abnormalities in tumour DNA replication, or by testing tumours using immunohistochemistry (IHC) for loss of expression of proteins involved in MMR (i.e., MLH1, MSH2, MSH6, and PMS2) as a precursor to gene sequencing. Recent literature suggests that testing tumours for loss of protein expression is as accurate as microsatellite analysis, while being cheaper and simpler to perform, and having the advantage of identifying the defective MMR gene to guide further genetic testing.7–10 Depending on the protein lost, additional tumour tests can be used to exclude likely non-inherited MMR deficiencies prior to embarking on germline gene sequencing.11 In a subset of CRC patients for whom the tumour IHC analysis reveals a lack of MLH1 protein expression, a somatic (non-inherited) event is often responsible for the tumour MMR deficiency. These cases are due to somatically acquired hypermethylation of the MLH1 promotor, which is seen in the presence of somatic BRAF V600E mutations. Therefore, additional testing for the BRAF V600E (as an indicator of the likelihood of MLH1 promoter methylation) or direct MLH1 promotor methylation can be used as part of diagnostic tumour testing algorithms to exclude likely sporadic CRC cases.11 These tests can be conducted simultaneously with the initial IHC, or they can be ordered automatically upon an initial test result indicative of dMMR (reflex testing).
