Exome sequencing points to pathogenic ATM variants in gastric cancer

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

doi:10.1038/s41431-025-01994-8

Exome sequencing points to pathogenic ATM variants in gastric cancer

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^*

^*Corresponding author for this work

University of Marburg
Karolinska Institutet
Leipzig University
University Lille
IRCCS Ospedale Casa Sollievo della Sofferenza - San Giovanni Rotondo (FG)
Instituto Português de Oncologia do Porto Francisco Gentil E.P.E.
Medical University of Łódź
Fondazione Policlinico Universitario “A. Gemelli” IRCCS
Catholic University of the Sacred Heart
Medical University of Lublin
University of Cologne
Centro de Investigacion Biomedica en Red
Hospital Clinico Universitario Zaragoza
Instituto Aragones de Ciencias de la Salud, Zaragoza
Krankenhaus Nordwest, Frankfurt am Main
Hospices civils de Lyon
Aix-Marseille Université
Hopital Haut Leveque Pessac
CHU Montpellier
Hôpital Pontchaillou
University of the Basque Country
Hospital Clinic de Barcelona
University of Bonn
IRCCS Centro di Riferimento Oncologico - Aviano PN
University of Trieste
ASST of Cremona
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Charité – Universitätsmedizin Berlin
Ciber of Epidemiology and Public Health CIBERESP
Public Health Division
Research Department of the Portuguese League Against Cancer-North (LPCC-NRNorte)
Riga East University Hospital
Digestive Diseases Centre GASTRO
Lithuanian University of Health Sciences
IIS Aragón
Otto von Guericke University Magdeburg

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Number of pages	6
Journal	European Journal of Human Genetics
DOIs	https://doi.org/10.1038/s41431-025-01994-8
Publication status	Accepted/In press - 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

OECD Field of Science

3.2 Clinical Medicine

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10.1038/s41431-025-01994-8

Cite this

Koebbe, L. L., Hess, T., Haas, S. L., Gockel, I., Piessen, G., Latiano, A., Pereira, C., Malecka-Wojciesko, E., Mokrowiecka, A., Boccia, S., Majewski, M., Alakus, H., Lanas, Á., Pastorino, R., Goetze, T. O., Elbe, P., Kreuser, N., Palmieri, O., Tavano, F., ... Schumacher, J. (Accepted/In press). Exome sequencing points to pathogenic ATM variants in gastric cancer. European Journal of Human Genetics. https://doi.org/10.1038/s41431-025-01994-8

@article{c994a2c09bed4c25949eceaa6c8a5e93,

title = "Exome sequencing points to pathogenic ATM variants in gastric cancer",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41431-025-01994-8",

language = "English",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

}

Koebbe, LL, Hess, T, Haas, SL, Gockel, I, Piessen, G, Latiano, A, Pereira, C, Malecka-Wojciesko, E, Mokrowiecka, A, Boccia, S, Majewski, M, Alakus, H, Lanas, Á, Pastorino, R, Goetze, TO, Elbe, P, Kreuser, N, Palmieri, O, Tavano, F, Bruns, CJ, Glehen, O, B. D’Journo, X, Gronnier, C, Fabre, JM, Sulpice, L, Bujanda, L, Moreira, L, Heilmann-Heimbach, S, Billmann, M, Noethen, MM, Cannizzaro, R, Ghidini, M, Hamann, L, Aragones, N, Dinis-Ribeiro, M, Medeiros, R, Al-Batran, SE, Leja, M, Kupcinskas, J, García-González, MA, Maj, C, Venerito, M & Schumacher, J 2025, 'Exome sequencing points to pathogenic ATM variants in gastric cancer', European Journal of Human Genetics. https://doi.org/10.1038/s41431-025-01994-8

TY - JOUR

T1 - Exome sequencing points to pathogenic ATM variants in gastric cancer

AU - Koebbe, Laura L.

AU - Hess, Timo

AU - Haas, Stephan L.

AU - Gockel, Ines

AU - Piessen, Guillaume

AU - Latiano, Anna

AU - Pereira, Carina

AU - Malecka-Wojciesko, Ewa

AU - Mokrowiecka, Anna

AU - Boccia, Stefania

AU - Majewski, Marek

AU - Alakus, Hakan

AU - Lanas, Ángel

AU - Pastorino, Roberta

AU - Goetze, Thorsten Oliver

AU - Elbe, Peter

AU - Kreuser, Nicole

AU - Palmieri, Orazio

AU - Tavano, Francesca

AU - Bruns, Christiane Josephine

AU - Glehen, Olivier

AU - B. D’Journo, Xavier

AU - Gronnier, Caroline

AU - Fabre, Jean M.

AU - Sulpice, Laurent

AU - Bujanda, Luis

AU - Moreira, Leticia

AU - Heilmann-Heimbach, Stefanie

AU - Billmann, Maximilian

AU - Noethen, Markus M.

AU - Cannizzaro, Renato

AU - Ghidini, Michele

AU - Hamann, Lutz

AU - Aragones, Nuria

AU - Dinis-Ribeiro, Mário

AU - Medeiros, Rui

AU - Al-Batran, Salah Eddin

AU - Leja, Mārcis

AU - Kupcinskas, Juozas

AU - García-González, María A.

AU - Maj, Carlo

AU - Venerito, Marino

AU - Schumacher, Johannes

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

UR - https://www.nature.com/articles/s41431-025-01994-8

UR - https://www.scopus.com/pages/publications/105026273335

U2 - 10.1038/s41431-025-01994-8

DO - 10.1038/s41431-025-01994-8

M3 - Article

C2 - 41454052

AN - SCOPUS:105026273335

SN - 1018-4813

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

ER -

Exome sequencing points to pathogenic ATM variants in gastric cancer

Abstract

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OECD Field of Science

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