Frequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma

Karoliina Tuppurainen (1) , Laura Pukkila (1) , Anne Tuomisto (2) , Rami Kuivila (1) , Tiina Kantola (1) , Päivi H Sirniö (1) , Tuomo J Karttunen (1) , Markus Mäkinen (3, 4)

1 Institute of Diagnostics, Department of Pathology
2 Department of Pathology
3 Department of Pathology
4 Department of Pathology

Aims: To define the occurrence of KRAS and BRAF mutations, microsatellite instability (MSI), MGMT and hMLH1 methylation and expression in colorectal serrated adenocarcinoma. Methods: KRAS codon 12/13 and 59/61 and BRAFV600E mutations, MSI, MGMT and hMLH1 methylation and expression in 42 serrated adenocarcinomas and 17 serrated adenomas was compared with 59 non-serrated CRCs and 9 adenomas. Results: KRAS and BRAF mutations were observed in 45% and 33% of serrated adenocarcinomas and in 27% and 0% of non-serrated CRCs (p<0.001). KRAS c12G→A transition was the predominant type of mutation in serrated adenocarcinomas. BRAF-mutated serrated adenocarcinomas were MSI-H in 42% (p=0.075), showed hMLH1 (100%;p=0.001) and MGMT methylation (90.9%;p=0.019). Fifty-six percent of MSS/MSI-L serrated adenocarcinomas harboured KRAS mutations. In non-serrated cancers, KRAS mutations did not associate with MSI status. Conclusions: High combined mutation rate (79-82%) of KRAS and BRAF in serrated adenomas and adenocarcinomas indicates that MAPK activation is a crucial part of serrated pathway. BRAF mutations are specific for serrated adenocarcinoma, and identify a subset of serrated adenocarcinomas with gene methylation and a tendency for MSI-H. High frequency of KRAS mutations in serrated adenocarcinomas suggests that a significant proportion of KRAS-mutated CRCs originate from serrated precursors, thus challenging the traditional Vogelstein's model.

Mots clés: Medicine

Karoliina Tuppurainen, Laura Pukkila, Anne Tuomisto, Rami Kuivila, Tiina Kantola, et al.. Frequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma. Histopathology, 2011, 58 (5), pp.679. ⟨10.1111/j.1365-2559.2011.03821.x⟩. ⟨hal-00628683⟩