SETD6 dominant negative mutation in familial colorectal cancer type X

Abstract

Familiar colorectal cancer type X (FCCTX) comprises families that fulfill the Amsterdam criteria for hereditary non-polyposis colorectal cancer, but that lack the mismatch repair deficiency that defines the Lynch syndrome. Thus, the genetic cause that increases the predisposition to colorectal and other related cancers in families with FCCTX remains to be elucidated. Using whole-exome sequencing, we have identified a truncating mutation in the SETD6 gene (c.791_792insA, p.Met264IlefsTer3) in all the affected members of a FCCTX family. SETD6 is a mono-methyltransferase previously shown to modulate the NF-κB and Wnt signaling pathways, among other. In the present study, we characterized the truncated version of SETD6, providing evidence that this SETD6 mutation may play a role in the cancer inheritance in this family. Here we demonstrate that the truncated SETD6 lacks its enzymatic activity as a methyltransferase, while maintaining other properties such as its expression, localization and substrate-binding ability. In addition, we show that the mutant allele is expressed and that the resulting protein competes with the wild type for their substrates, pointing to a dominant negative nature. These findings suggest that the identified mutation impairs the normal function of SETD6, which may result in the deregulation of the different pathways in which it is involved, contributing to the increased susceptibility to cancer in this FCCTX family.

PAK4 methylation by the methyltransferase SETD6 attenuates cell adhesion

“…1B and Supplementary Fig. S1B) SETD6 was auto-methylated, which is consistent with our previous knowledge describing the enzymatic activity of SETD6 [21][22][23] . We tested the methylation of PAK4 K473R mutant also in cells, using a pan-methyl antibody that identified methylated wild-type Flag PAK4 but not the K473R mutant (Fig.…”

Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine

“…Although the scant available data suggest high penetrance for RSP20 mutations and absence of extracolonic manifestations, data from additional mutation carriers are required to estimate risks and recommend surveillance measures. Many other putative familial CRC genes have been proposed, but most are extremely uncommon and others may only moderately increase the risk of CRC, complicating the assessment of their contribution to predisposition to CRC .…”

Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries

“…Four BRCA2 variants containing c.502C>A p. (Pro168Thr), c.927A>G p. (=), c.5744C>T p. (Thr1915Met), and c.7759C>T p. (Leu2587Phe) show cosegregation with FCCX and may exert a function as susceptibility alleles in FCCX families [ 74 ]. A truncating dominant negative mutation in SETD6 also provides a possible explanation for the cancer predisposition of one FCCX family [ 75 ]. Germline variants in the semaphorin 4A gene increase the predisposition to colorectal cancers in families with FCCX [ 76 ].…”