Candidate susceptibility variants for esophageal squamous cell carcinoma

Abstract

Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life-time risk of ESCC, but no other well-established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth. We collected archival tissue material and exome sequenced a total of 30 ESCC cases. We prioritized shared, deleterious and rare variants that were significantly enriched in our sample set compared to Finnish and population subset specific controls. Six variants passed filtering, the most frequent being a nonsense mutation in DNAH9 (p.Tyr1573Ter) found in four unrelated patients. DNAH9 has been reported to be frequently lost in ESCC tumors. In this study, one patient's tumor showed loss of the wild type allele of DNAH9 suggesting a tumor suppressive function. A missense variant in GKAP1 was shared by three patients, and missense variants in BAG1, NFX1, FUK, and DDOST by two each. EP300 which has previously been implicated in the genesis of ESCC had a missense variant segregating in three affected individuals in a single family. If validated in independent patient sets, these variants could serve as a tool towards prevention and early diagnosis of ESCC.

Identification of proteins associated with development of metastasis from cutaneous squamous cell carcinomas (cSCCs) via proteomic analysis of primary cSCCs*

“…46 Furthermore, another study investigating susceptibility variants for oesophageal SCC reported missense variants in DDOST in two cases. 47 The mechanism whereby DDOST permits metastasis is unclear, but it may involve protein glycosylation and the impact of this via various biological processes relevant to cancer. 48 For example, DDOST functions as a subunit for an accessory protein required for stabilization of the STT3 protein subunits of oligosaccharyltransferase (OST), 49,50 which promotes tumour immune evasion via PD ligand 1 (PD-L1).…”

Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma

“…For a brief description of the pipeline used on the raw sequencing data, please refer to Donner et al 2017 [17].…”

From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers—A Multidisciplinary Perspective

“…Interestingly inactivating mutations clustered in defined geographic areas, being more frequent in those ECSSs which affect North American patients than in those aroused in Chinese population. Moreover, germline mutations in the RHBDF2 gene (17q25) which cause tylosis (focal non-epidermolytic palmoplantar keratoderma) have been reported to be markers of genetic familial susceptibility for the early onset of ESSC [ 49 , 50 , 51 ].…”