Reflex immunohistochemistry (rIHC) to detect mismatch repair deficiency (dMMR) is a recommended screening tool for the detection of Lynch Syndrome (LS) in incident colorectal cancers (CRCs). Additional BRAF testing in tumours exhibiting MLH1 loss can help exclude sporadic cases, which do not require CGS. IHC is increasingly performed as the dMMR phenotype may be considered both a prognostic and predictive biomarker. The downstream management of dMMR results can be complex and patients are not always referred to clinical genetic services (CGS).
We investigated the work-up of dMMR CRC patients detected between 2005-2013 at two academic institutes. During this period centre 1 performed IHC only at physician request and centre 2 implemented rIHC in November 2008. Neither performed additional BRAF testing prior to CGS referral. Patients who did not receive a CGS referral were identified. Ethical approval was obtained and retrospective BRAF testing was performed on tissue from patients who were still alive and whose tumours exhibited loss of MLH1.
During the studied period, 2169 new CRC patients were reviewed. 87 (4%) of these were identified as dMMR CRCs. 39(45%) patients were referred and investigated for LS. Forty-seven patients were not referred. The characteristics of these patients are shown in table 1. 41 of 47 (87%) patients had tumours with evidence of MLH1 loss, 35 of these were older than 70 years. Nineteen patients had died and BRAF testing is on-going in this cohort. 14 had a BRAFV600E mutation and 8 were wild-type. Only 2 of these were less than 70 years. These patients will now be offered genetic counselling.
|N (47) %|
|Median Age (yrs.)||78yrs (55-90)|
|MMR protein loss|
Over half of identified patients were not referred to clinical genetic services. Braf testing can enrich the appropriate patients requiring referral and thus improve the efficiency of screening. Certain patients with BRAF-wild type tumours require additional work-up.
Clinical trial identification
Legal entity responsible for the study
St James Hospital
All authors have declared no conflicts of interest.