Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer

Abstract

<i>Mitogen-activated protein kinase kinase 1 (MAP2K1)</i> is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in <i>ERK</i>. <i>MAP2K1</i> mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of <i>MAP2K1</i> mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 <i>MAPK</i> mutant and 50 <i>MAPK</i> wildtype cases each), we found one <i>MAP2K1</i> mutation each in PTC and CRC, both of which were <i>MAPK</i> wildtype. We further analyzed 286 PTC and 289 CRC <i>MAPK</i> wildtype cases and found three <i>MAP2K1</i> mutant PTC cases and two <i>MAP2K1</i> mutant CRC cases. Thus, the overall prevalence of <i>MAP2K1</i> mutation in <i>MAPK</i> wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four <i>MAP2K1</i> mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring <i>MAP2K1</i> mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of <i>MAP2K1</i> somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of <i>MAP2K1</i> and <i>MAPK</i> mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through <i>MAPK</i> signaling pathway.