Premium
Targeted next generation sequencing of MLH1 ‐deficient, MLH1 promoter hypermethylated, and BRAF / RAS ‐wild‐type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions
Author(s) -
Vaňková Bohuslava,
Vaněček Tomáš,
Ptáková Nikola,
Hájková Veronika,
Dušek Martin,
Michal Michael,
Švajdler Peter,
Daum Ondřej,
Daumová Magdaléna,
Michal Michal,
Mezencev Roman,
Švajdler Marián
Publication year - 2020
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22861
Subject(s) - mlh1 , kras , microsatellite instability , cancer research , colorectal cancer , biology , cancer , gene , dna mismatch repair , genetics , microsatellite , allele
Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter ( MLH1 ph), and/or the presence of microsatellite instability, and BRAF / KRAS wild‐type status ( BRAFwt / KRASwt ). In this study, we used targeted next generation sequencing (NGS) to explore the occurence of potentially therapeutically targetable gene fusions in an unselected series of BRAFwt / KRAS wt CRC cases that displayed MLH1d/ MLH1 ph. From the initially identified group of 173 MLH1d CRC cases, 141 cases (81.5%) displayed MLH1 ph. BRAFwt/RASwt genotype was confirmed in 23 of 141 (~16%) of MLH1d/ MLH1 ph cases. Targeted NGS of these 23 cases identified oncogenic gene fusions in nine patients (39.1%; CI95: 20.5%‐61.2%). Detected fusions involved NTRK (four cases), ALK (two cases), and BRAF genes (three cases). As a secondary outcome of NGS testing, we identified PIK3K‐AKT‐mTOR pathway alterations in two CRC cases, which displayed PIK3CA mutation. Altogether, 11 of 23 (~48%) MLH1d/ MLH1 ph/ BRAFwt/RASwt tumors showed genetic alterations that could induce resistance to anti‐EGFR therapy. Our study confirms that targeted NGS of MLH1d/ MLH1 ph and BRAFwt / RASwt CRCs could be a cost‐effective strategy in detecting patients with potentially druggable oncogenic kinase fusions.