Identification of Rare Noncoding Variants in Familial Nonmedullary Thyroid Carcinoma

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Familial nonmedullary thyroid carcinoma (FNMTC) has high heritability but unknown genetic drivers.
• Papillary thyroid carcinoma (PTC) is the most common type of NMTC.
• Understanding genetic determinants in NMTC families is crucial.

Purpose of the Study:

• Investigate the role of rare noncoding germline variants in FNMTC etiology.
• Identify novel genetic factors contributing to familial thyroid cancer.
• Develop a framework for noncoding variant analysis in FNMTC.

Main Methods:

• Leveraged whole-genome sequencing (WGS) data from 17 PTC families.
• Applied a filtering strategy for noncoding variants in regulatory regions.
• Analyzed expression/splicing quantitative trait loci and thyroid enhancers.
• Ranked variants by predicted pathogenicity and performed Sanger sequencing.

Main Results:

• Selected 121 variants based on in-silico prediction and custom ranking.
• Identified 56 variants that cosegregated in PTC-affected individuals.
• Found candidate variants in families without previously identified protein-coding variants.

Conclusions:

• Noncoding variants play a significant role in FNMTC etiology.
• A novel approach for identifying noncoding germline variants was established.
• Further functional studies are required to elucidate variant pathogenicity mechanisms.