BRAF testing in a South African cohort of MLH1 deficient endometrial carcinomas: lessons learnt

Introduction Endometrial carcinomas are common female genital tract malignancies. Western countries identified BRAF mutations in very few endometrial carcinomas, whilst an Eastern study documented mutations in one-fifth of endometrial carcinomas. We aimed to assess BRAF mutations in an ethnically mixed South African patient population using immunohistochemistry (IHC), polymerase chain reaction (PCR) and Sanger sequencing in relation to MLH1 methylation. Methods A total of 145 endometrioid endometrial carcinoma cases were retrieved from departmental archives and underwent MLH1, MSH2, MSH6 and PMS2 IHC testing. The 37 cases that showed MLH1 loss underwent BRAF IHC, PCR and Sanger sequencing. Results Six out of 37 cases demonstrated BRAF mutations: 4 were identified by PCR, whilst IHC and Sanger sequencing identified one mutation each. Three PCR mutations were at the V600E codon, whilst 1 case had a V600D mutation. Agreement between IHC versus overall BRAF mutational status, and sequencing versus overall mutational status, was 86.49% (p-value < 0.005). There was agreement of 94.59% between PCR and overall mutational status with statistically significant, moderate non-random concordance (kappa = 0.77, p = 0.0001). Discussion BRAF mutations were identified in 16.21% of cases, which is higher than frequencies noted in Western studies, but less than in an Eastern study. There was no association between MLH1 methylation and BRAF status in endometrial carcinomas from our patient population (kappa = −0.0223, p = 0.6649). Our results in endometrial carcinomas, similar to findings from Western studies, indicate that BRAF mutations are not beneficial in distinguishing which patients have spontaneously occurring tumours from those who may harbour germline mutations and are suspected of having Lynch syndrome.