Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer Lamis Yehia, Farshad.

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Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer Lamis Yehia, Farshad Niazi, Ying Ni, Joanne Ngeow, Madhav Sankunny, Zhigang Liu, Wei Wei, Jessica L. Mester, Ruth A. Keri, Bin Zhang, Charis Eng The American Journal of Human Genetics Volume 97, Issue 5, Pages 661-676 (November 2015) DOI: 10.1016/j.ajhg.2015.10.001 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of CS-Affected Family 616 The pedigree of CS-affected family 616 is shown with the presence of wild-type (−) or c.1781T>G (p.Val594Gly) mutant (+) SEC23B alleles. Symbols are as follows: square, male; circle, female; black fill, affected; slash, deceased. The proband (III-2) for whom whole-exome sequencing was performed is indicated by an arrow. Roman numerals represent generation number, and Arabic numerals represent individuals within each generation. Affected members show various types of CS-related cancers, including thyroid (II-4, III-2, III-4, and IV-1), breast (II-2 and II-3), endometrial (IV-4), skin (III-5), and both thyroid and breast (I-4) cancers. Age at diagnosis is indicated between parentheses. Abbreviations are as follows: TC, thyroid cancer; BT, benign thyroid; BC, breast cancer; EC, endometrial cancer; SC, skin cancer. The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Germline SEC23B Mutation Spectra in CS and Apparently Sporadic CS-Related Cancers from TCGA A schematic of SEC23B and its functional domains is shown; Arabic numerals correspond to amino acid number. The amino acid positions corresponding to germline heterozygous variants are indicated for variants identified in CS-affected family 616 (blue), an unrelated CS proband (gray), TCGA apparently sporadic thyroid cancer (black), breast cancer (pink), endometrial cancer (purple), and a shared variant observed in all three cancer types and in CS (green). Abbreviations are as follows: ZNF, zinc finger domain; BS, beta-sandwich. The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Lymphoblastoid Cells Derived from Family 616 Show No Differences in SEC23B Transcript and Protein Levels between p.Val594Gly Carriers and Wild-Type Individuals (A) qRT-PCR expression showed no notable trend in SEC23B transcript expression between wild-type individuals and variant carriers. Values are normalized to unaffected individual III-3 and represent three technical replicates for which data represent mean values ± SEM. ∗∗p < 0.01, ∗p < 0.05 (two-sided Student’s t test). (B) SEC23B levels and quantification by western blot. PTEN-mutation-positive lymphoblastoid cells (LCLs) from other CS individuals were also used as internal exploratory controls. 1019XX, 1202XX, and 4406XX represent healthy control LCLs unrelated to the pedigree. SEC23B-mutation carriers from the pedigree are indicated by asterisks in each panel. “aa” refers to the amino acids targeted by the SEC23B antibody. The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Cellular and Biochemical Characterization of Family 616 Variant p.Val594Gly in a Normal Thyroid Cell Line (A) Normal thyroid Nthy-ori 3-1 cells were stably transduced with wild-type and mutant c.1781T>G (p.Val594Gly) SEC23B fused with GFP. Wild-type cells (Nthy-SEC23B-WT) showed SEC23B localization typical of ER proteins, whereas a subset of mutant cells (Nthy-SEC23B-V594G) showed aberrant aggregation of SEC23B. Scale bars represent 20 μm. (B) Western blot and densitometric analysis of overexpressed SEC23B, endogenous SEC23B and paralog SEC23A, and GAPDH (loading control) from stable cell lines. Wild-type and mutant Nthy-SEC23B-V594G cells showed similar levels of SEC23B and SEC23A. The Nthy-EGFP cell line was used as a negative control to indicate baseline levels of SEC23B and SEC23A in the cell line (no SEC23B overexpression in these cells). Exogenous SEC23B-GFP normalized to the wild-type, and endogenous SEC23B and SEC23A normalized to levels in the Nthy-EGFP cell line. The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 5 The SEC23B c.1781T>G (p.Val594Gly) Variant Confers Neoplastic Phenotypes upon ER Stress (A) Representative images of invaded Nthy-SEC23B-WT (left) and Nthy-SEC23B-V594G (right) cells in a Transwell assay after overnight serum starvation. Invaded cells were counted after 24 hr in quadruplicate fields of view in triplicate membranes. Data represent mean values ± SEM. ∗∗∗p < 0.001 (two-sided Student’s t test). (B) Gelatin zymography was performed with conditioned media from wild-type and mutant cells and showed more MMP-2 and MMP-9 activity in supernatant originating from Nthy-SEC23B-V594G (right lanes) than in supernatant from Nthy-SEC23B-WT (left lanes) cells. Data represent triplicate lanes with band intensity normalized to protein mass. Data represent mean values ± SEM. ∗∗∗p < 0.001, ∗p < 0.05 (two-sided Student’s t test). (C) Wild-type and mutant cells were treated with 1 μM thapsigargin (TG) for the induction of ER stress. Large colonies of cells expressing altered SEC23B formed, after which both Nthy-SEC23B-WT and Nthy-SEC23B-V594G cells were fixed and stained with Giemsa, and colonies were counted. Stained colonies represent cells 14 days after treatment, and a colony is standardly defined as a cluster of ≥50 cells. Data shown represent three independent experiments done in triplicate for each genotype. Data represent mean values ± SEM. ∗∗∗p < 0.001 (two-sided Student’s t test). (D) Treatment of wild-type and mutant cells with 0.1 μg/ml tunicamycin (TM), another ER-stress-inducing agent, resulted in more growth of mutant cells than of wild-type cells. Data shown represent two independent experiments done in triplicate for each genotype at each time point. Data represent pooled mean values ± SEM. ∗∗∗p < 0.001, ∗∗p < 0.01 (two-sided Student’s t test). The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 6 SEC23B Germline Heterozygous Variants Cause Predisposition to Hereditary and Apparently Sporadic Cancers Abbreviations are as follows: CS, Cowden syndrome; TG, thapsigargin; TM, tunicamycin. The American Journal of Human Genetics 2015 97, 661-676DOI: (10.1016/j.ajhg.2015.10.001) Copyright © 2015 The American Society of Human Genetics Terms and Conditions