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.
PY - 2020/5/1
Y1 - 2020/5/1
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.
AB - 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.
KW - ESCC
KW - Genetic variant
KW - Hereditary disease
KW - Next-generation sequencing
KW - Signaling pathway
UR - http://www.scopus.com/inward/record.url?scp=85069502552&partnerID=8YFLogxK
U2 - 10.1007/s12094-019-02174-z
DO - 10.1007/s12094-019-02174-z
M3 - Article
C2 - 31321674
AN - SCOPUS:85069502552
VL - 22
SP - 681
EP - 693
JO - Clinical and Translational Oncology
JF - Clinical and Translational Oncology
SN - 1699-048X
IS - 5
ER -