Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

Computational Oncology National Center for Tumor Diseases Molecular Diagnostics Program Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Pilsen Czechia

Medical Faculty Heidelberg University Heidelberg Germany

Preclinical Pediatric Oncology Hopp Children's Cancer Center Heidelberg Germany

Unit of Medical Genetics Department of Medical and Surgical Sciences S Orsola Malphigi Hospital University of Bologna Bologna Italy

Zobrazit více v PubMed

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2018) 68:394–424. 10.3322/caac.21492 PubMed DOI

Mazeh H, Sippel RS. Familial nonmedullary thyroid carcinoma. Thyroid (2013) 23:1049–56. 10.1089/thy.2013.0079 PubMed DOI

Bonora E, Tallini G, Romeo G. Genetic predisposition to familial nonmedullary thyroid cancer: an update of molecular findings and state-of-the-art studies. J Oncol (2010) 2010:385206. 10.1155/2010/385206 PubMed DOI PMC

Charkes ND. On the prevalence of familial nonmedullary thyroid cancer in multiply affected kindreds. Thyroid (2006) 16:181–6. 10.1089/thy.2006.16.181 PubMed DOI

El Lakis M, Giannakou A, Nockel PJ, Wiseman D, Gara SK, Patel D, et al. . Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery (2019) 165:50–7. 10.1016/j.surg.2018.05.075 PubMed DOI PMC

Fallah M, Pukkala E, Tryggvadottir L, Olsen JH, Tretli S, Sundquist K, et al. . Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries. J Med Genet (2013) 50:373–82. 10.1136/jmedgenet-2012-101412 PubMed DOI

Hincza K, Kowalik A, Kowalska A. Current knowledge of germline genetic risk factors for the development of non-medullary thyroid cancer. Genes (Basel) (2019) 10(7):482. 10.3390/genes10070482 PubMed DOI PMC

Peiling Yang S, Ngeow J. Familial non-medullary thyroid cancer: unraveling the genetic maze. Endocr Relat Cancer (2016) 23:R577–95. 10.1530/ERC-16-0067 PubMed DOI

Capezzone M, Cantara S, Marchisotta S, Filetti S, De Santi MM, Rossi B, et al. . Short telomeres, telomerase reverse transcriptase gene amplification, and increased telomerase activity in the blood of familial papillary thyroid cancer patients. J Clin Endocrinol Metab (2008) 93:3950–7. 10.1210/jc.2008-0372 PubMed DOI

Srivastava A, Kumar A, Giangiobbe S, Bonora E, Hemminki K, Forsti A, et al. . Whole genome sequencing of familial non-medullary thyroid cancer identifies germline alterations in MAPK/ERK and PI3K/AKT signaling pathways. Biomolecules (2019) 9(10):605. 10.3390/biom9100605 PubMed DOI PMC

Roeb W, Higgins J, King MC. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet (2012) 21:2738–44. 10.1093/hmg/dds101 PubMed DOI PMC

Wang Y, Dai B, Ye D. CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med (2015) 8:15708–15. PubMed PMC

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (2009) 25:1754–60. 10.1093/bioinformatics/btp324 PubMed DOI PMC

Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg SRF, Consortium WGS, et al. . Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet (2014) 46:912–8. 10.1038/ng.3036 PubMed DOI PMC

Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, et al. . A global reference for human genetic variation. Nature (2015) 526:68–74. 10.1038/nature15393 PubMed DOI PMC

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. . Analysis of protein-coding genetic variation in 60,706 humans. Nature (2016) 536:285–91. 10.1038/nature19057 PubMed DOI PMC

Smigielski EM, Sirotkin K, Ward M, Sherry ST. dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res (2000) 28:352–5. 10.1093/nar/28.1.352 PubMed DOI PMC

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res (2010) 38:e164. 10.1093/nar/gkq603 PubMed DOI PMC

Kumar A, Bandapalli OR, Paramasivam N, Giangiobbe S, Diquigiovanni C, Bonora E, et al. . Familial cancer variant prioritization pipeline version 2 (FCVPPv2) applied to a papillary thyroid cancer family. Sci Rep (2018) 8:11635. 10.1038/s41598-018-29952-z PubMed DOI PMC

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet (2014) 46:310–5. 10.1038/ng.2892 PubMed DOI PMC

Cooper GM, Stone EA, Asimenos G, Program NCS, Green ED, Batzoglou S, et al. . Distribution and intensity of constraint in mammalian genomic sequence. Genome Res (2005) 15:901–13. 10.1101/gr.3577405 PubMed DOI PMC

Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res (2010) 20:110–21. 10.1101/gr.097857.109 PubMed DOI PMC

Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. . Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res (2005) 15:1034–50. 10.1101/gr.3715005 PubMed DOI PMC

Liu X, Wu C, Li C, Boerwinkle E. dbNSFP v3.0: A One-Stop Database of Functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat (2016) 37:235–41. 10.1002/humu.22932 PubMed DOI PMC

Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PloS Genet (2013) 9:e1003709. 10.1371/journal.pgen.1003709 PubMed DOI PMC

Robinson JT, Thorvaldsdottir H, Wenger AM, Zehir A, Mesirov JP. Variant review with the integrative genomics viewer. Cancer Res (2017) 77:e31–4. 10.1158/0008-5472.CAN-17-0337 PubMed DOI PMC

Papadopoulos JS, Agarwala R. COBALT: constraint-based alignment tool for multiple protein sequences. Bioinformatics (2007) 23:1073–9. 10.1093/bioinformatics/btm076 PubMed DOI

Hecht M, Bromberg Y, Rost B. Better prediction of functional effects for sequence variants. BMC Genomics (2015) 16:S1. 10.1186/1471-2164-16-S8-S1 PubMed DOI PMC

Pires DEV, Ascher DB, Blundell TL. mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics (Oxford . England) (2014) 30:335–42. 10.1093/bioinformatics/btt691 PubMed DOI PMC

Velankar S, Alhroub Y, Alili A, Best C, Boutselakis HC, Caboche S, et al. . PDBe: protein data bank in Europe. Nucleic Acids Res (2011) 39:D402–10. 10.1093/nar/gkq985 PubMed DOI PMC

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. . STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res (2019) 47:D607–d613. 10.1093/nar/gky1131 PubMed DOI PMC

Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, et al. . Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet (2003) 72:270–80. 10.1086/346094 PubMed DOI PMC

Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, et al. . Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. EMBO J (2006) 25:3179–90. 10.1038/sj.emboj.7601209 PubMed DOI PMC

Boissier P, Huynh-Do U. The guanine nucleotide exchange factor Tiam1: a Janus-faced molecule in cellular signaling. Cell Signal (2014) 26:483–91. 10.1016/j.cellsig.2013.11.034 PubMed DOI

Mertens AE, Roovers RC, Collard JG. Regulation of Tiam1-Rac signalling. FEBS Lett (2003) 546:11–6. 10.1016/S0014-5793(03)00435-6 PubMed DOI

Jin J, Cai L, Liu ZM, Zhou XS. miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev (2013) 14:3681–4. 10.7314/APJCP.2013.14.6.3681 PubMed DOI

Li J, Liang S, Jin H, Xu C, Ma D, Lu X. Tiam1, negatively regulated by miR-22, miR-183 and miR-31, is involved in migration, invasion and viability of ovarian cancer cells. Oncol Rep (2012) 27:1835–42. 10.3892/or.2012.1744 PubMed DOI

Minard ME, Kim LS, Price JE, Gallick GE. The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat (2004) 84:21–32. 10.1023/B:BREA.0000018421.31632.e6 PubMed DOI

Sanmartín E, Yáñez Y, Fornés-Ferrer V, Zugaza JL, Cañete A, Castel V, et al. . TIAM1 variants improve clinical outcome in neuroblastoma. Oncotarget (2017) 8:45286–97. 10.18632/oncotarget.16787 PubMed DOI PMC

Shi YL, Miao RZ, Cheng L, Guo XB, Yang B, Jing CQ, et al. . Up-regulation of T-lymphoma and metastasis gene 1 in gastric cancer and its involvement in cell invasion and migration. Chin Med J (Engl) (2013) 126:640–5. 10.3760/cma.j.issn.0366-6999.20122167 PubMed DOI

Worthylake DK, Rossman KL, Sondek J. Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Nature (2000) 408:682–8. 10.1038/35047014 PubMed DOI

Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, et al. . Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet (2012) 21:2899–911. 10.1093/hmg/dds116 PubMed DOI PMC

Ribadeneyra C, Amin S. EWSR1 potentially functions as an RNA chaperone in the stress response. FASEB J (2016) 30:594.3–3. 10.1096/fasebj.30.1_supplement.594.3 DOI

Paronetto MP, Minana B, Valcarcel J. The Ewing sarcoma protein regulates DNA damage-induced alternative splicing. Mol Cell (2011) 43:353–68. 10.1016/j.molcel.2011.05.035 PubMed DOI

Wang X, Zeng L, Wang J, Chau JF, Lai KP, Jia D, et al. . A positive role for c-Abl in Atm and Atr activation in DNA damage response. Cell Death Differ (2011) 18:5–15. 10.1038/cdd.2010.106 PubMed DOI PMC

Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer