Mutational Landscape of Colorectal Tumors From Individuals With Unexplained Adenomatous or Serrated Colorectal Polyposis.
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Sommer Anna K, Te Paske Iris B A W, Jansen Erik A M, Gschwind Axel, Demidov German, Steinke-Lange Verena, Spier Isabel, Steyaert Wouter, Yaldiz Burcu, Steehouwer Marloes, Hommerding Oliver, Dietrich Dimo, Peters Sophia, Garcia-Pelaez José, Laner Andreas, Oliveira Carla, Capellá Gabriel, Nagtegaal Iris D, Bläker Hendrik, Ellwanger Kornelia, Hoischen Alexander, Gilissen Christian, van der Post Rachel S, Kristiansen Glen, Hoogerbrugge Nicoline, Ossowski Stephan, Valle Laura, Holinski-Feder Elke, Ligtenberg Marjolijn J L, Aretz Stefan, de Voer Richarda M
Аннотация
METHODS: We performed whole-exome sequencing of colorectal tumors (n = 299) from 153 individuals with adenomatous or serrated polyposis and 16 individuals with early-onset colorectal cancer in the absence of known pathogenic germline variants. Subsequently, somatic mutations were called and a driver gene analysis for pathogenicity was performed. In addition, CpG island methylator phenotypes, tumor mutational burden, microsatellite instability, and mutational signatures were analyzed and compared with publicly available datasets of molecularly profiled colorectal cancers and polyps.
RESULTS: Somatic mutations in APC/CTNNB1 and BRAF were significantly more frequent in adenomatous and serrated polyps, respectively. APC mosaicism was identified in 19% of individuals with adenomatous polyposis. In 9% of serrated polyps, a CpG island methylator phenotypes high methylation status was detected. Almost all polyps presented with a low tumor mutational burden and the majority were microsatellite stable. In APC/CTNNB1- and BRAF-mutated polyps, we identified a significantly lower contribution of the clock-like signature SBS1 and a significantly higher contribution of the normal colon tissue signature SBS89, respectively, compared with sporadic colorectal tumors.
CONCLUSIONS: Our results indicate that BRAF-mutated serrated polyps are molecularly more similar to normal colon tissue than APC- and/or CTNNB1-mutated tumors. Overall, molecular tumor profiling of individuals with polyposis contributes to understanding the genetic disease etiology.