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Molecular Phenotypes and Potential Therapeutic Targets in Esophagogastric Adenocarcinoma Unearthed by Whole Genome and Transcriptome Analyses

Windon, A.; Al Assaad, M.; Kevin, K.; Mendelson, N.; Hissong, E.; Deshpande, A.; Tranquille, M.; Mclee, J.; Patel, M.; Medina-Martinez, J. S.; Chiu, K.; Manohar, J.; Sigouros, M.; Ocean, A.; Sboner, A.; Jessurun, J.; Elemento, O.; Shah, M.; Mosquera, J. M.

2024-07-08 oncology
10.1101/2024.07.08.24310077 medRxiv
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BackgroundEsophagogastric adenocarcinoma demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are invisible to other sequencing platforms, and analyzed their potential clinical ramification. MethodsOur study employed state-of-the-art analyses of whole genome and transcriptome sequencing on 52 matched tumor and germline samples from 47 patients, aiming to unravel new therapeutic targets and deepen our understanding of these cancers molecular foundations. ResultsThe analyses revealed 88 targetable oncogenic mutations and fusions in 62% of the patients, and further elucidated molecular signatures associated with mismatch repair and homologous recombination deficiency. Notably, we identified CDK12-type genomic instability associated with CDK12 fusions, novel NTRK, NRG1, ALK, and MET fusions, and structural variants in relevant cancer genes like RAD51B. ConclusionsOur findings demonstrate the power of integrative whole genome and transcriptome sequencing in identifying additional therapeutic targets, supporting a promising path for precision medicine in treating esophagogastric adenocarcinoma.

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