Unraveling the genetic landscape of susceptibility to multiple primary cancers
Pooja Middha,
Linda Kachuri,
Jovia L. Nierenberg,
Rebecca E. Graff,
Taylor B. Cavazos,
Thomas J. Hoffmann,
Jie Zhang,
Stacey Alexeeff,
Laurel Habel,
Douglas A. Corley,
Stephen Van Den Eeden,
Lawrence H. Kushi,
Elad Ziv,
Lori C. Sakoda,
John S. Witte
Affiliations
Pooja Middha
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Linda Kachuri
Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA
Jovia L. Nierenberg
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
Rebecca E. Graff
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Taylor B. Cavazos
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
Thomas J. Hoffmann
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
Jie Zhang
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Stacey Alexeeff
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Laurel Habel
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Douglas A. Corley
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Stephen Van Den Eeden
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Lawrence H. Kushi
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Elad Ziv
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
Lori C. Sakoda
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
John S. Witte
Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA; Corresponding author
Summary: With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (p < 5 × 10−8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when compared with single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.
