Integrative screening identifies functional variants and VNTRs underlying GWAS signals at the 5p15.33 multi-cancer susceptibility locus
Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the <i>CLPTM1L</i> signal marked by rs465498) with CRISPRi revealed opposing effects on <i>TERT</i> expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic <i>CLPTM1L</i> variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.
Authors
- Irene Collins (ORCID: https://orcid.org/0000-0001-5434-4659)
- Katelyn E. Connelly (ORCID: https://orcid.org/0000-0002-1693-5519)
- Ashley Jermusyk (ORCID: https://orcid.org/0000-0003-1553-039X)
- Wen Luo (ORCID: https://orcid.org/0000-0002-3558-4136)
- Alison Patricia Klein (ORCID: https://orcid.org/0000-0003-2737-8399)
- Mark M. Iles (ORCID: https://orcid.org/0000-0002-2603-6509)
- Matthew H. Law (ORCID: https://orcid.org/0000-0002-4303-8821)
- Kristine M. Jones (ORCID: https://orcid.org/0000-0003-1584-8920)
- Brian M. Wolpin (ORCID: https://orcid.org/0000-0002-0455-1032)
- R. Hung
- Karen Funderburk
- Hayley Sowards (ORCID: https://orcid.org/0000-0003-4054-2173)
- Hyunkyung Kong
- Brenen W. Papenberg (ORCID: https://orcid.org/0000-0003-3734-3018)
- Jason W. Hoskins (ORCID: https://orcid.org/0000-0001-6944-1996)
- Rebecca C. Hennessey (ORCID: https://orcid.org/0000-0002-5283-6147)
- Jianxin Shi (ORCID: https://orcid.org/0000-0001-8606-4707)
- Harsh Patel (ORCID: https://orcid.org/0000-0002-9860-8254)
- Aidan O’Brien (ORCID: https://orcid.org/0000-0003-2188-4223)
- Jun Zhong (ORCID: https://orcid.org/0000-0001-9963-5396)
- Michelle Ho (ORCID: https://orcid.org/0000-0002-9143-2241)
- Oscar Florez-Vargas
- Minal Patel
- Manal M. Hassan (ORCID: https://orcid.org/0000-0002-8413-449X)
- Rohit Thakur
- Jiyeon Choi
- Mai Xu
- Thong Minh Luong
- Timothy Myers
- Kevin M Brown
- Sudipto Das
- Rachael Z Stolzenberg-Solomon
- Laufey T. Amundadottir
Institutions
- Queen's University Belfast (GB)
- University of Leeds (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Inserm (FR)
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- University of New Mexico (US)
- University of Washington (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- QIMR Berghofer Medical Research Institute (AU)
- Université Paris Sciences et Lettres (FR)
- Jacksonville College (US)
- Fred Hutch Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Dana-Farber/Harvard Cancer Center (US)
- National Cancer Institute (US)
- Mayo Clinic in Florida (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Centre international de recherche sur le cancer (FR)
- Division of Cancer Epidemiology and Genetics
Publication Details
- Journal
- medRxiv
- Published
- 2026-03-04
- DOI
- https://doi.org/10.64898/2026.03.03.26347427
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 0.00