title: Germline genetics of cancer of unknown primary (CUP) and its specific subtypes.
abstract: Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10-7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5'UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Plastic and Reconstructive Surgery, Skane University Hospital, Malmö, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Manjer
authors.affiliation: Department of Medical Biosciences/Pathology, University of Umea, Umea, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Clinical Pharmacology, Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Pettersson-Kymmer
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Medical Department I, University Hospital Carl Gustav Carus, University Cancer Center, Dresden, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Löffler
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009382:Neoplasms, Unknown Primary / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: SNP; genetic risk factors; genotype; germline genetics; hidden primary cancer