BRAF Mutations May Be Driver of Colonic Neuroendocrine Carcinoma

A study exploring the genetic underpinnings of the newly classified high-grade neuroendocrine carcinoma has found that it is a rare but aggressive tumor with a high frequency of BRAF mutations, according to results published in the Journal of Surgical Oncology.

According to the study, in 2010 the World Health Organization reclassified gastrointestinal (GI) neuroendocrine neoplasms into two categories: neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). These classifications are based on mitosis and proliferative rates. Advancements in whole-genome sequencing has increased understanding of the genetic basis of GI NETs, but little is known about the underlying mechanisms of NECs.

“Due to the high incidence of BRAF mutations in our series of GI NECs and the presence of mutations involving the RAS-MAP kinase pathway,” wrote Kamran Idrees, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues, “treating these patients with BRAF/MEK inhibitor therapy is worth further clinical investigation.”

In this study, Idrees and colleagues performed whole exome sequencing of nine patients with colonic NEC from January 2005 to June 2013. Sequencing was done on tumor DNA from two patients with an 80% or greater tumor cellularity and available matched normal tissue. In these two patients, the researchers identified BRAF exon 15 mutations.

“Because we identified BRAF mutations in both NEC samples and because BRAF mutations have been implicated in carcinogenesis, and are actionable in other diseases, we hypothesized that BRAF mutations could be oncogenic drivers of high grade GI NECs,” the researchers wrote. “We therefore queried the mutational status of BRAF exons 11 and 15 in an additional seven patients with GI NECs.”

Analysis was performed via sanger sequencing of BRAF exons 11 and 15; they showed BRAF V600E mutations in two of the seven specimens (29%).

Overall, BRAF exon 15 mutations were found in four of the nine colonic NECs (44%). The researchers noted that all three cases found with BRAF V600E mutations were large-cell NECs; the case with a BRAF D594G mutation was a small-cell carcinoma.

“Further investigation into the VEGFR, chromatin remodeling, and apoptotic pathways is also warranted as our analysis revealed several mutations in these targetable pathways,” the researchers wrote.