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Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies
Author(s) -
Jesinghaus Moritz,
Pfarr Nicole,
Kloor Matthias,
Endris Volker,
Tavernar Luca,
Muckenhuber Alexander,
von Knebel Doeberitz Magnus,
Penzel Roland,
Weichert Wilko,
Stenzinger Albrecht
Publication year - 2016
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.22330
Subject(s) - kras , genotyping , genetic heterogeneity , biology , mlh1 , microsatellite instability , colorectal cancer , metastasis , microsatellite , cancer research , genetics , computational biology , gene , genotype , cancer , dna mismatch repair , allele , phenotype
Synchronous colorectal carcinomas (sCRC) are clinically challenging neoplasms. Although the epidemiological characteristics are quite well established, their biological basis is still poorly understood. Hence, we performed comprehensive molecular profiling of 23 sCRC cases comprising 50 synchronous primary tumors, 5 metastases, and corresponding normal tissue by targeted deep sequencing of 30 CRC‐related genes, microsatellite analysis and analysis for methylated MLH1 . We identified a striking inter‐ and intratumoral genetic heterogeneity of sCRC. Twenty (87%) cases showed genetic heterogeneity leaving only three cases with tumors that had an identical genetic make‐up. Intertumoral heterogeneity was frequently observed for clinically actionable genes, including KRAS . Specifically, 44% of the cases harbored tumors of which at least one was KRAS mutated and the other KRAS wildtype. Moreover, 48% of the cases had at least double, sometimes even triple or quadruple mutations in KRAS , APC , TP5 3, PIK3CA , and TGFBR2 , most of them being subclonal events. Lastly, we detected four cases (17%) with microsatellite instable (MSI) tumors with one case harboring one MSI‐ and a distinct microsatellite stable carcinoma. Our data demonstrate a striking genetic heterogeneity not only between different sCRC of a single case but also within a single tumor. These results contribute to the biological understanding of sCRC and directly impact genotyping strategies and oncological decision making. Testing one tumor or a single metastasis may not suffice in the sCRC setting as clinically relevant and tumor‐specific genetic information may be left undetected compromising optimal oncological therapy. © 2015 Wiley Periodicals, Inc.