| Summary: | Somatic mutation profile of thyroid cancer in dogs has not been investigated. We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious mutations in the TPO gene associated with the disease predisposition. In this study, we comprehensively investigated the somatic mutations in the tumors that potentially contribute to the inherited tumor formation and development using high depth whole-genome sequencing. A GNAS A204D missense mutation was identified in 4 of 7 tumors by whole-genome sequencing and xx of 36 FCC tumors by PCR-RFLP. In humans, somatic mutations in the GNAS gene were also identified but in low prevalence. Meanwhile, the homologous mutation has not been reported. It suggested the potential interaction between germline risk factor and driver mutation by comparing to prevalence of GNAS mutations in human samples. Moreover, tumors with GNAS A204D mutation had significantly less somatic SNVs and Indels, suggesting that this mutation could be a marker for less malignant form of thyroid tumor in dogs. Abstract Background We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale. Results Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs’ tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic ...
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