Oncotarget

Research Papers:

Germline genetics of cancer of unknown primary (CUP) and its specific subtypes

Kari Hemminki _, Bowang Chen, Abhishek Kumar, Olle Melander, Jonas Manjer, Göran Hallmans, Ulrika Pettersson-Kymmer, Claes Ohlsson, Gunnar Folprecht, Harald Löffler, Alwin Krämer and Asta Försti

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Oncotarget. 2016; 7:22140-22149. https://doi.org/10.18632/oncotarget.7903

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Abstract

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

Correspondence to:

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

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.


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