Assessing thyroid cancer risk using polygenic risk scores.

• Published in: Proceedings of the National Academy of Sciences
• Main Authors: Liyanarachchi, Sandya, Gudmundsson, Julius, Ferkingstad, Egil, He, Huiling, Jonasson, Jon G, Tragante, Vinicius, Asselbergs, Folkert W, Xu, Li, Kiemeney, Lambertus A, Netea-Maier, Romana T, Mayordomo, Jose I, Plantinga, Theo S, Hjartarson, Hannes, Hrafnkelsson, Jon, Sturgis, Erich M, Brock, Pamela, Nabhan, Fadi, Thorleifsson, Gudmar, Ringel, Matthew D, Stefansson, Kari, de la Chapelle, Albert
• Other Authors: 1Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. 2Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. 3Department of Population Genomics, deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland. 4Department of Pathology, Landspitali-University Hospital, 101 Reykjavik, Iceland. 5Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. 6Department of Epidemiology, The Icelandic Cancer Registry, 105 Reykjavik, Iceland. 7Department of Cardiology, Heart and Lung Division, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands. 8Durrer Center for Cardiovascular Research, Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands. 9Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, WC1E 6BT London, United Kingdom. 10Farr Institute of Health Informatics Research, University College London, NW1 2DA London, United Kingdom. 11Institute of Health Informatics, University College London, NW1 2DA London, United Kingdom. 12Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 13Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 14Radboud Institute for Health Sciences, Radboud University Medical Centre, 6500HB Nijmegen, The Netherlands. 15Division of Endocrinology, Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud University Medical Centre, 6500HB Nijmegen, The Netherlands. 16UCHealth Diane O'Connor Thompson Breast Center, University of Colorado Hospital, Aurora, CO 80045. 17Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB Nijmegen, The Netherlands. 18Head&Neck Surgery Department, Landspitali-University Hospital, 101 Reykjavik, Iceland. 19Department of Oncology, Landspitali-University Hospital, 101 Reykjavik, Iceland. 20Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. 21Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210. 22Department of Population Genomics, deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland; [e-mail] [e-mail]. 23Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; [e-mail] [e-mail].
• Format: Article in Journal/Newspaper
• Language: English
• Published: National Academy of Sciences 2020
• Subjects: GWAS; polygenic risk score; risk prediction; thyroid cancer; Skjaldkirtill; Skjaldkirtilssjúkdómar; Krabbamein; Thyroid Neoplasms; Genome-Wide Association Study; Iceland
• Online Access: http://hdl.handle.net/2336/621368; https://doi.org/10.1073/pnas.1919976117

To access publisher's full text version of this article click on the hyperlink below Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI)