HGG Advances (Jul 2021)

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

  • Hongjie Chen,
  • Arunabha Majumdar,
  • Lu Wang,
  • Siddhartha Kar,
  • Kevin M. Brown,
  • Helian Feng,
  • Constance Turman,
  • Joe Dennis,
  • Douglas Easton,
  • Kyriaki Michailidou,
  • Jacques Simard,
  • Timothy Bishop,
  • Iona C. Cheng,
  • Jeroen R. Huyghe,
  • Stephanie L. Schmit,
  • Tracy A. O’Mara,
  • Amanda B. Spurdle,
  • Puya Gharahkhani,
  • Johannes Schumacher,
  • Janusz Jankowski,
  • Ines Gockel,
  • Melissa L. Bondy,
  • Richard S. Houlston,
  • Robert B. Jenkins,
  • Beatrice Melin,
  • Corina Lesseur,
  • Andy R. Ness,
  • Brenda Diergaarde,
  • Andrew F. Olshan,
  • Christopher I. Amos,
  • David C. Christiani,
  • Maria T. Landi,
  • James D. McKay,
  • Myriam Brossard,
  • Mark M. Iles,
  • Matthew H. Law,
  • Stuart MacGregor,
  • Jonathan Beesley,
  • Michelle R. Jones,
  • Jonathan Tyrer,
  • Stacey J. Winham,
  • Alison P. Klein,
  • Gloria Petersen,
  • Donghui Li,
  • Brian M. Wolpin,
  • Rosalind A. Eeles,
  • Christopher A. Haiman,
  • Zsofia Kote-Jarai,
  • Fredrick R. Schumacher,
  • Paul Brennan,
  • Stephen J. Chanock,
  • Valerie Gaborieau,
  • Mark P. Purdue,
  • Paul Pharoah,
  • Rayjean J. Hung,
  • Laufey T. Amundadottir,
  • Peter Kraft,
  • Bogdan Pasaniuc,
  • Sara Lindström

Journal volume & issue
Vol. 2, no. 3
p. 100041

Abstract

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Summary: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

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