Germline genetics of cancer of unknown primary (CUP) and its specific subtypes
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Kari Hemminki1,2, Bowang Chen1, Abhishek Kumar1, Olle Melander3, Jonas Manjer4, Göran Hallmans5, Ulrika Pettersson-Kymmer6, Claes Ohlsson7, Gunnar Folprecht8, Harald Löffler9, Alwin Krämer9, Asta Försti1,2
1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Center for Primary Health Care Research, Lund University, Malmö, Sweden
3Department of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden
4Department of Plastic and Reconstructive Surgery, Skane University Hospital, Malmö, Sweden
5Department of Medical Biosciences/Pathology, University of Umea, Umea, Sweden
6Clinical Pharmacology, Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, Sweden
7Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
8Medical Department I, University Hospital Carl Gustav Carus, University Cancer Center, Dresden, Germany
9Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany
Kari Hemminki, e-mail: [email protected]
Keywords: hidden primary cancer, SNP, genotype, germline genetics, genetic risk factors
Received: February 12, 2016 Accepted: February 23, 2016 Published: March 03, 2016
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.
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