SEC23B and Cowden Syndrome

Cowden syndrome (CS) is an autosomal-dominant cancer-predisposing disorder characterized by elevated risks of epithelial tumors, notably thyroid carcinoma. Despite known predisposing genes, ~50% of CS cases remain unexplained. In a multi-generation CS family, whole-exome and Sanger sequencing identified a heterozygous SEC23B missense variant, c.1781T>G (p.Val594Gly), which co-segregated with disease across three affected relatives (segregation LOD not shown) ([PMID:26522472]).

Subsequently, germline heterozygous SEC23B variants were found in 3/96 (3%) unrelated CS probands negative for known predisposition genes and in The Cancer Genome Atlas thyroid cancer cohort, indicating enrichment in apparently sporadic thyroid cancers ([PMID:26522472]). These data support a dominant-acting predisposition mechanism rather than the recessive loss-of-function seen in congenital dyserythropoietic anemia type II.

Functional analyses in a normal thyroid cell line demonstrated that the p.Val594Gly variant provokes endoplasmic reticulum (ER) stress and drives cell-colony formation, survival, invasive growth, and oncogenic phenotypes, consistent with a gain-of-function or neomorphic mechanism ([PMID:26522472]). This aligns with ER stress ‘‘addiction’’ models of tumorigenesis where SEC23B variants hijack COPII pathway dynamics to favor malignant transformation.

No reports to date have refuted the SEC23B–Cowden syndrome association, and convergence of genetic co-segregation, variant enrichment in independent cohorts, and concordant functional data solidifies this link. Additional large-scale case–control studies could further quantify variant penetrance and spectrum.

In summary, germline heterozygous SEC23B variants, notably c.1781T>G (p.Val594Gly), are moderately validated as CS predisposition alleles via autosomal-dominant inheritance. Testing for SEC23B variants should be considered in mutation-negative CS patients, especially those with thyroid carcinoma at a young age.

Key Take-home: SEC23B heterozygous variants represent a clinically actionable moderate-strength predisposition factor in Cowden syndrome, guiding genetic testing and surveillance strategies.

References

• American journal of human genetics • 2015 • Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer PMID:26522472

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