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Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes.

Abstract

PURPOSE

Esophageal squamous cell carcinoma (ESCC) is one of the most important causes of mortality in the developing world. Although hereditary forms arise from germ-line mutations in TP53, Rb, and the mismatch repair genes, many familial cases present with an unknown inherited cause. The new theory of rare, high-penetrance mutations in less known genes is a likely explanation for the underlying predisposition in some of these familial cases.

METHODS

Exome sequencing was performed in 9 patients with esophageal squamous cancer from 9 families with strong disease aggregation without mutations in known hereditary esophageal cancer genes. Data analysis was limited to only really rare variants (0-0.01%), producing a putative loss of function and located in genes with a role compatible with carcinogenesis.

RESULTS

Twenty-two final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDK11A, ARID1A, JMJD6, MAML3, CDKN2AIP, and PHLDA1.

CONCLUSION

Together, we identified new potential esophageal squamous cancer predisposition variants in genes which may have a role in cancer and are involved in chromatin remodeling and cell-cycle pathway, which could increase the risk of ESCC.

Authors+Show Affiliations

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA.Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Abbaszadeganmr@mums.ac.ir. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Abbaszadeganmr@mums.ac.ir.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31321674

Citation

Golyan, F F., et al. "Whole-exome Sequencing of Familial Esophageal Squamous Cell Carcinoma Identified Rare Pathogenic Variants in New Predisposition Genes." Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 2019.
Golyan FF, Druley TE, Abbaszadegan MR. Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes. Clin Transl Oncol. 2019.
Golyan, F. F., Druley, T. E., & Abbaszadegan, M. R. (2019). Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes. Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, doi:10.1007/s12094-019-02174-z.
Golyan FF, Druley TE, Abbaszadegan MR. Whole-exome Sequencing of Familial Esophageal Squamous Cell Carcinoma Identified Rare Pathogenic Variants in New Predisposition Genes. Clin Transl Oncol. 2019 Jul 18; PubMed PMID: 31321674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes. AU - Golyan,F F, AU - Druley,T E, AU - Abbaszadegan,M R, Y1 - 2019/07/18/ PY - 2019/04/16/received PY - 2019/06/28/accepted PY - 2019/7/20/entrez KW - ESCC KW - Genetic variant KW - Hereditary disease KW - Next-generation sequencing KW - Signaling pathway JF - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico JO - Clin Transl Oncol N2 - PURPOSE: Esophageal squamous cell carcinoma (ESCC) is one of the most important causes of mortality in the developing world. Although hereditary forms arise from germ-line mutations in TP53, Rb, and the mismatch repair genes, many familial cases present with an unknown inherited cause. The new theory of rare, high-penetrance mutations in less known genes is a likely explanation for the underlying predisposition in some of these familial cases. METHODS: Exome sequencing was performed in 9 patients with esophageal squamous cancer from 9 families with strong disease aggregation without mutations in known hereditary esophageal cancer genes. Data analysis was limited to only really rare variants (0-0.01%), producing a putative loss of function and located in genes with a role compatible with carcinogenesis. RESULTS: Twenty-two final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDK11A, ARID1A, JMJD6, MAML3, CDKN2AIP, and PHLDA1. CONCLUSION: Together, we identified new potential esophageal squamous cancer predisposition variants in genes which may have a role in cancer and are involved in chromatin remodeling and cell-cycle pathway, which could increase the risk of ESCC. SN - 1699-3055 UR - https://www.unboundmedicine.com/medline/citation/31321674/Whole-exome_sequencing_of_familial_esophageal_squamous_cell_carcinoma_identified_rare_pathogenic_variants_in_new_predisposition_genes L2 - https://dx.doi.org/10.1007/s12094-019-02174-z DB - PRIME DP - Unbound Medicine ER -