Candidate susceptibility variants for esophageal squamous cell carcinoma

Area of Science:

• Genetics
• Oncology
• Cancer Research

Background:

• Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is a significant global health concern with high mortality.
• While familial aggregation and heritability are noted in ESCC, only RHBDF2 mutations (causing tylosis) are established predisposition genes.
• The identification of novel susceptibility genes for ESCC is crucial for understanding its etiology and improving patient outcomes.

Purpose of the Study:

• To identify novel candidate susceptibility variants for esophageal squamous cell carcinoma (ESCC).
• To investigate the genetic basis of familial aggregation in ESCC.
• To explore potential genetic markers for early diagnosis and prevention strategies.

Main Methods:

• Utilized Finnish Population Information System and cancer registry data to identify ESCC patient cohorts.
• Clustered patients by family name and municipality of birth to identify potential familial links.
• Performed exome sequencing on 30 ESCC cases and analyzed shared, rare, and deleterious variants against population controls.

Main Results:

• Six candidate variants passed filtering, with a frequent nonsense mutation in DNAH9 (p.Tyr1573Ter) identified in four unrelated ESCC patients.
• One tumor exhibited loss of the wild-type DNAH9 allele, supporting a potential tumor suppressor role.
• Additional variants were found in GKAP1, BAG1, NFX1, FUK, DDOST, and EP300, with some showing familial segregation.

Conclusions:

• The identified variants, particularly in DNAH9, represent potential novel susceptibility factors for ESCC.
• These findings may contribute to a better understanding of ESCC heritability and genetic predisposition.
• Validation in independent cohorts could establish these variants as tools for ESCC prevention and early detection.