Inherited variants in genes somatically mutated in thyroid cancer

• Published in: PloS one 2017-04, Vol.12 (4), p.e0174995-e0174995
• Main Authors: Campo, Chiara, Köhler, Aleksandra, Figlioli, Gisella, Elisei, Rossella, Romei, Cristina, Cipollini, Monica, Bambi, Franco, Hemminki, Kari, Gemignani, Federica, Landi, Stefano, Försti, Asta
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; 5' Untranslated Regions; Adenomatous Polyposis Coli Protein - genetics; Alleles; Amino acids; Analysis; Biology and Life Sciences; Cancer and Oncology; Cancer och onkologi; Case-Control Studies; Chromogranins - genetics; Clinical Medicine; Development and progression; European Continental Ancestry Group - genetics; Female; Gene mutation; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genotype; GTP-Binding Protein alpha Subunits, Gs - genetics; Health aspects; Health risk assessment; Humans; Italy; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine and Health Sciences; Middle Aged; Mutation; Odds Ratio; People and Places; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Promoters; Research and Analysis Methods; Thyroid; Thyroid cancer; Thyroid Neoplasms - etiology; Thyroid Neoplasms - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174995

Tumour suppressor genes when mutated in the germline cause various cancers, but they can also be somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic well-differentiated thyroid cancer (WDTC). We performed a two-stage case-control association study with a total of 2214 cases and 2108 healthy controls from an Italian population. By genotyping 34 single nucleotide polymorphisms (SNPs), we covered a total of 59 missense SNPs and SNPs located in the 5' and 3' untranslated regions (UTRs) of 10 different genes. The Italian1 series showed a suggestive association for 8 SNPs, from which three were replicated in the Italian2 series. The meta-analysis revealed a study-wide significant association for rs459552 (OR: 0.84, 95%CI: 0.75-0.94) and rs1800900 (OR: 1.15, 95%CI: 1.05-1.27), located in the APC and GNAS genes, respectively. The APC rs459552 is a missense SNP, located in a conserved amino acid position, but without any functional consequences. The GNAS rs1800900 is located at a conserved 5'UTR and according to the experimental ENCODE data it may affect promoter and histone marks in different cell types. The results of this study yield new insights on WDTC, showing that inherited variants in the APC and GNAS genes can play a role in the etiology of thyroid cancer. Further studies are necessary to better understand the role of the identified SNPs in the development of WDTC and to functionally validate our in silico predictions.