Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Julie Guibon,Mojgan Karimi,Constance Xhaard,Carole Rubino,Claire Mulot,Florent De Vathaire,Claire Schvartz,Céline Besse,Anne Boland,Evgenia Ostroumova,Frédérique Rachédi,Fabienne Lesueur,Yan Ren,Om Kulkarni,Pascal Guénel,Thérèse Truong,Ausrele Kesminiene,Marie‐Christine Boutron‐Ruault ,Rosa María Bravo Ortiz ,Jean‐François Deleuze ,Delphine Bacq‐Daian ,Anne‐Valérie Guizard ,Pierre Laurent‐Puig ,Élisabeth Adjadj ,Pierre‐Emmanuel Sugier

doi:10.18632/oncotarget.27888

Abstract

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality.At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue.Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

Highlights

Thyroid cancer (TC) is the most common endocrine malignancy
We used data from EPITHYR consortium in which genome-wide association studies (GWAS) data was available for 1,855 cases and 2,321 controls of Europeans, Polynesians and Melanesians ancestries
The few GWAS conducted so far allowed the identification of several differentiated thyroid carcinoma (DTC) susceptibility loci with the strongest associations located on 2q35, 9q22.33, 8p12 and 14q13.3

Summary

Introduction

Thyroid cancer (TC) is the most common endocrine malignancy. Its incidence has been rising over the past few decades and varies considerably around the world. Elevated incidence was reported in some Pacific islands such as French Polynesia and New-Caledonia, two French territories, with estimated incidence rates in 2018 being 27.7/100,000 and 25.6/100,000 person-years (PY) in women and 6.5/100 000 and 7.6/100 000 PY in men [1], respectively. Ethnic differences in incidence have been reported in New-Caledonia with higher rates among Melanesians than in other ethnic groups [2]. Apart from exposure to ionizing radiation during childhood which is the only wellestablished risk factor, DTC risk has been consistently associated with obesity [3]. Other risk factors such as deficiency or excess of iodine levels [4] or some hormonal and reproductive factors are suspected [5]. We recently conducted a GWAS in EPITHYR that confirmed the susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12, and suggested novel signals at 1p31.3 and 16q23.2 [14]

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Conclusion