Susceptibility Gene Identified for Familial Nonmedullary Thyroid Cancer


Key Points

  • Affected family members were heterozygous for the HABP2 G534E variant.
  • The variant was present in 4.7% of 423 patients with papillary thyroid cancer.

As reported in The New England Journal of Medicine, Gara et al identified a germline HABP2 mutation as a susceptibility gene for familial nonmedullary thyroid cancer.

Identification of HABP2 Variant

In a kindred study, whole-exome sequencing was performed using peripheral blood DNA from affected family members and unaffected spouses to identify single-nucleotide variants and insertions and deletions segregating with all affected members but not present in unaffected spouses. A HABP2 single-nucleotide variant in exon 13 was found to segregate with all seven affected members, including four initially diagnosed with thyroid cancer through screening.

The HABP2 variant features a G/A substitution at base 1601, with a change from glycine to glutamate at position 534 (G534E). All affected members were heterozygous for this variant.

Analysis of The Cancer Genome Atlas data on 423 patients with papillary thyroid cancer showed that 4.7% had the HABP2 G534E variant vs 0.7% of persons with unknown disease status in multiethnic population databases (P < .001).

Loss of Function

The G534E variant was associated with increased HABP2 protein expression in tumor samples from affected family members vs normal adjacent thyroid tissue and vs samples from sporadic cancers. Functional studies showed that HABP2 has a tumor-suppressive effect, with the G534E variant resulting in loss of function.

Electron Kebebew, MD, of the National Cancer Institute, is the corresponding author for the New England Journal of Medicine article.

The study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.