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<p>Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in <i>CDH1</i> and <i>ATM</i> were enriched among GC cases. Beyond GC, <i>ATM</i> LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, <i>ATM</i> should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with <i>ATM</i> PVs occur alongside GC.</p>

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Exome sequencing points to pathogenic ATM variants in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Laura L. Koebbe,
  • Timo Hess,
  • Stephan L. Haas,
  • Ines Gockel,
  • Guillaume Piessen,
  • Anna Latiano,
  • Carina Pereira,
  • Ewa Malecka-Wojciesko,
  • Anna Mokrowiecka,
  • Stefania Boccia,
  • Marek Majewski,
  • Hakan Alakus,
  • Ángel Lanas,
  • Roberta Pastorino,
  • Thorsten Oliver Goetze,
  • Peter Elbe,
  • Nicole Kreuser,
  • Orazio Palmieri,
  • Francesca Tavano,
  • Christiane Josephine Bruns,
  • Olivier Glehen,
  • Xavier B. D’Journo,
  • Caroline Gronnier,
  • Jean M. Fabre,
  • Laurent Sulpice,
  • Luis Bujanda,
  • Leticia Moreira,
  • Stefanie Heilmann-Heimbach,
  • Maximilian Billmann,
  • Markus M. Noethen,
  • Renato Cannizzaro,
  • Michele Ghidini,
  • Lutz Hamann,
  • Nuria Aragones,
  • Mário Dinis-Ribeiro,
  • Rui Medeiros,
  • Salah-Eddin Al-Batran,
  • Mārcis Leja,
  • Juozas Kupcinskas,
  • María A. García-González,
  • Carlo Maj,
  • Marino Venerito,
  • Johannes Schumacher

摘要

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in CDH1 and ATM were enriched among GC cases. Beyond GC, ATM LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, ATM should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with ATM PVs occur alongside GC.