Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer

Am J Hum Genet. 2015 Nov 5;97(5):661-76. doi: 10.1016/j.ajhg.2015.10.001. Epub 2015 Oct 29.


Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ∼50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. We also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation-negative CS probands with thyroid cancer and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that the TCGA thyroid cancer dataset is enriched with unique germline deleterious SEC23B variants associated with a significantly younger age of onset. SEC23B encodes Sec23 homolog B (S. cerevisiae), a component of coat protein complex II (COPII), which transports proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Interestingly, germline homozygous or compound-heterozygous SEC23B mutations cause an unrelated disorder, congenital dyserythropoietic anemia type II, and SEC23B-deficient mice suffer from secretory organ degeneration due to ER-stress-associated apoptosis. By characterizing the p.Val594Gly variant in a normal thyroid cell line, we show that it is a functional alteration that results in ER-stress-mediated cell-colony formation and survival, growth, and invasion, which reflect aspects of a cancer phenotype. Our findings suggest a different role for SEC23B, whereby germline heterozygous variants associate with cancer predisposition potentially mediated by ER stress "addiction."

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Adhesion
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Exome / genetics
  • Female
  • Fluorescent Antibody Technique
  • Follow-Up Studies
  • Genotype
  • Germ-Line Mutation / genetics*
  • Hamartoma Syndrome, Multiple / genetics*
  • Hamartoma Syndrome, Multiple / metabolism
  • Hamartoma Syndrome, Multiple / pathology*
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Pedigree
  • Phenotype
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology*
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism
  • Vesicular Transport Proteins / physiology
  • Young Adult


  • RNA, Messenger
  • SEC23B protein, human
  • SEC23B protein, mouse
  • Vesicular Transport Proteins

Associated data

  • SRA/SRP059300