Analysis of genetic predisposition to familial non-medullary thyroid cancer by whole genome sequencing.

BACKGROUND

Several putative susceptibility genes for familial papillary thyroid carcinoma, or familial non-medullary thyroid carcinoma (FNMTC), have been identified. However, in most families the molecular basis for FNMTC remains elusive.

METHODS

Two families with≥3 first-degree relatives in≥2 generations and≥2 unaffected relatives were selected. Germline DNA from 2 patients and 2 unaffected individuals per family were analyzed by whole genome sequencing. All individuals were genotyped for putative pathogenic variants by Sanger sequencing, and minor allele frequency (MAF) was determined in 179 PTC-free European controls and the GnomAD database. Methylation analysis of candidate genes was carried out by EPIC BeadChips or pyrosequencing on germline and tumoral DNA.

RESULTS

Heterozygous variants in cancer-related genes expressed in thyroid tissue and predicted to impact protein function were identified in patients from both families. In F8, the best candidate was the P2RX5 p.Leu32Gln variant previously reported in another PTC family. However, its relatively high MAF in European controls (0.43%) casts doubt on its pathogenic role. In F17, the most relevant variant was c.345del in MST1R encoding the tyrosine kinase receptor RON. The variant is predicted to encode a truncated isoform. Further analysis of tumor and germline DNA showed no clear evidence of an expression switch from the long to the short oncogenic RON isoform.

CONCLUSION

Our data provide novel insight on the genetics of FNMTC. The P2RX5 p.Leu32Gln variant should be considered either as low-penetrant or not associated with PTC predisposition. MST1R appears as a new putative susceptibility gene for FNMTC that warrants further consideration.