Candidate susceptibility variants for esophageal squamous cell carcinoma.
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.
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Iikki
0000-0002-2957-8397
I
Donner
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Riku
R
Katainen
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Tomas
T
Tanskanen
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Eevi
E
Kaasinen
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Mervi
M
Aavikko
Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Kristian
K
Ovaska
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
Miia
M
Artama
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
Eero
E
Pukkala
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Lauri A
LA
Aaltonen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C580845:RHBDF2 protein, human