Identification of <scp> <i>BCL2L11</i> </scp> as a Candidate Gene for Hereditary Predisposition to Non‐Medullary Thyroid Cancer Using Familial Whole‐Exome‐Sequencing

Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, and increased risk of metastasis and recurrence. Although no high penetrance predisposing gene has been identified at present, the estimated contribution of genetics is significant. Our study explored five families presenting FNMTC using Whole-Exome Sequencing and found three candidate genes: TELO2 in one family, UACA and BCL2L11 in another. All of these tumor suppressor genes are expressed in the thyroid, exhibit under-expression in tumor tissue compared to healthy tissue both in silico and in our samples, and two of them are known to be involved in thyroid carcinogenesis via the FOXO3A pathway. Functional analysis to validate these candidate genes in thyroid cancer cells showed that one of the three, BCL2L11, has a tumor suppressor effect on proliferation and apoptosis. Their impact on hereditary predisposition to thyroid cancer, as well as their combined effects, requires further study. Indeed, a case-control study would be essential to determine the diagnostic utility of their routine analysis.