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

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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.

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Availability of data and materials

Imaging data could be provided upon request.

Abbreviations

ESCC:

Esophageal squamous cell carcinoma

WES:

Whole-exome sequencing

MAML3:

Mastermind-like 3

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Acknowledgements

We thank our colleagues in Avicenna research center for sharing information from data bank.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    F. F. Golyan & M. R. Abbaszadegan

  2. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    F. F. Golyan & M. R. Abbaszadegan

  3. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    T. E. Druley

Authors
  1. F. F. Golyan
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  2. T. E. Druley
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  3. M. R. Abbaszadegan
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Contributions

FFG and MRA design the experiment, analysis the data, and FFG and TED draft the paper for the work. MRA and TED help to revise the paper critically for important intellectual content. MRA did the financial support, review, and final approval of the paper to be published. All authors read and approved the final manuscript.

Corresponding author

Correspondence to M. R. Abbaszadegan.

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Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

This study was approved by the Mashhad University of Medical Science (MUMS).

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Patient consent was obtained prior to the initiation of the study.

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Golyan, F.F., Druley, T.E. & Abbaszadegan, M.R. Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes. Clin Transl Oncol 22, 681–693 (2020). https://doi.org/10.1007/s12094-019-02174-z

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  • DOI: https://doi.org/10.1007/s12094-019-02174-z

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