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Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood

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Author Manuscript Published OnlineFirst on October 30, 2019; DOI: 10.1158/1055-9965.EPI-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Common and rare sequence variants influencing tumor biomarkers in blood Sigurgeir Olafsson1, Kristjan F. Alexandersson1, Johann G.K. Gizurarson1, Katrin Hauksdottir1, Orvar Gunnarsson2, Karl Olafsson3, Julius Gudmundsson1, Simon N. Stacey1, Gardar Sveinbjornsson1, Jona Saemundsdottir1, Einar S. Bjornsson4,5, Sigurdur Olafsson4,6, Sigurdur Bjornsson4,7, Kjartan B. Orvar4,7, Arnor Vikingsson8,9, Arni J. Geirsson8,10,11, Sturla Arinbjarnarson12, Gyda Bjornsdottir1, Thorgeir E. Thorgeirsson1, Snaevar Sigurdsson1, Gisli H. Halldorsson1, Olafur T. Magnusson1, Gisli Masson1, Hilma Holm1, Ingileif Jonsdottir1,5, Olof Sigurdardottir13, Gudmundur I. Eyjolfsson11, Isleifur Olafsson14, Patrick Sulem1, Unnur Thorsteinsdottir1,5, Thorvaldur Jonsson5,15, Thorunn Rafnar1, Daniel F. Gudbjartsson1,16*, Kari Stefansson1,5,. 1deCODE genetics/AMGEN, Reykjavik, Iceland 2Department of Oncology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 3Department of Obstetrics and Gynecology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 4Department of Medicine, Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland 5Faculty of Medicine, University of Iceland, Reykjavik, Iceland 6Division of Gastroenterology and Hepatology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 7The Medical Center, Glaesibae, Reykjavik, Iceland 8Department of Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 9Thraut Fibromyalgia Clinic, Reykjavik, Iceland 10Center for Rheumatology Research, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 11Icelandic Medical Center (Laeknasetrid), Laboratory in Mjodd (RAM), Reykjavik, Iceland 12The Laboratory of the Medical Clinic Glaesibae, Reykjavik, Iceland 13Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland 14Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 15Department of Surgery, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 16School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. *To whom correspondence should be addressed. [email protected]. Address: Sturlugata 8, 101 Reykjavik, Iceland. Tel: +354 570-1900 1 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 30, 2019; DOI: 10.1158/1055-9965.EPI-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running title: GWAS of tumor biomarkers Keywords: Genome-wide association study, Cancer Antigens, Biomarkers, Alkaline phosphatase, Alpha-fetoprotein, Cancer Antigen 15.3, Cancer Antigen 19.9, Cancer Antigen 125, Carcinoembryonic antigen, Cancer registry Funding This study was funded by deCODE Genetics/Amgen and supported in part by the National Institute of Dental and Craniofacial Research of the National Institutes of Health, under award number R01DE022905, awarded to Dr. Kari Stefansson, [email protected]. Conflict of interest The authors that are affiliated with deCODE are employees of deCODE genetics/Amgen Inc. The other authors declare no conflict of interest. Nr of tables: 3 Nr of figures: 2 Words in abstract: 241 Word count (excluding abstract, acknowledgements, section headers and references): 3421 2 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 30, 2019; DOI: 10.1158/1055-9965.EPI-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Background: Alpha-fetoprotein, cancer antigens 15.3, 19.9, 125, carcinoembryonic antigen and 3 alkaline phosphatase are widely measured in attempts to detect cancer and to monitor 4 treatment response. However, due to lack of sensitivity and specificity, their utility is debated. 5 The serum levels of these markers are affected by a number of non-malignant factors, including 6 genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test 7 results for genetic effects. 8 Methods: We performed genome-wide association studies of serum levels of alpha-fetoprotein 9 (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 10 9,945) and 125 (N = 9,824), and alkaline phosphatase (N = 162,774). We also examined the 11 correlations between levels of these biomarkers and the presence of cancer, using data from a 12 nation-wide cancer registry. 13 Results: We report a total of 84 associations of 79 sequence variants with levels of the six 14 biomarkers, explaining between 2.3 and 42.3% of the phenotypic variance. Among the 79 15 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele 16 frequency less than 1%, 31 are coding variants and 7 are associated with gene expression in 17 whole blood. We also find multiple conditions associated with higher biomarker levels. 18 Conclusions: Our results provide insights into the genetic contribution to diversity in 19 concentration of tumor biomarkers in blood. 20 Impact: Genetic correction of biomarker values could improve prediction algorithms and 21 decision-making based on these biomarkers. 3 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 30, 2019; DOI: 10.1158/1055-9965.EPI-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 22 23 Introduction 24 Tumor biomarkers are substances or processes that can indicate the presence of cancer [1]. 25 Several tumor biomarkers are in clinical use for monitoring therapy but all lack the sensitivity 26 and specificity to be used for screening. However, recent advances in the detection of 27 circulating tumor DNA suggest that multi-analyte blood tests that combine an assay of 28 somatically mutated DNA (“liquid biopsy”) and protein and carbohydrate biomarkers in serum 29 have the potential to both find early cancer and to help determine its site of origin [2]. 30 In this work, we focused on six commonly measured biomarkers, namely alpha- 31 fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigens (CA) 15.3, 19.9 and 125, 32 and alkaline phosphatase (ALP). Measured in serum, these biomarkers are frequently used to 33 monitor status of disease, response to therapy and recurrence [1]. AFP is used as a biomarker 34 of hepatocellular carcinoma (HCC), endodermal sinus tumor of the ovary and non-seminoma 35 testicular germ cell tumors (TGCT) [3]. CEA has been used as a biomarker for colorectal cancer 36 [4]. CA-15.3 and CA-125 are mainly used as biomarkers of cancers of the breast and ovary, 37 respectively [5, 6], and CA-19.9 is used as a biomarker for pancreatic cancer [7]. We also include 38 ALP in our analysis because its levels are commonly elevated in cancers of the liver and bone 39 and when other cancers metastasize to these tissues [8]. However, the measurement of ALP in 40 serum is one of the most common blood tests ordered and we recognize that there are many 41 reasons for ALP measurements other than suspicion of- or monitoring of neoplasms. 42 Despite widespread use of these biomarkers in clinical practice, their low sensitivity and 43 specificity continue to cause controversy over their use [9-11]. As their levels are partially 4 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 30, 2019; DOI: 10.1158/1055-9965.EPI-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 44 determined by genetic factors, one approach to improve their sensitivity and specificity would 45 be to define “normal” values based on age, sex and genotype [2, 9]. We have previously 46 reported how genetic correction for variants affecting levels of prostate specific antigen (PSA) 47 results in personalized PSA cutoff value, which is more informative than a general cutoff value 48 when deciding to perform a prostate biopsy [12]. 49 The main goal of this study is to perform a genome-wide association study (GWAS) of 50 the levels of all six tumor biomarkers to identify sequence variants that affect baseline 51 biomarker levels, regardless of cancer diagnosis. We also describe the associations of the six 52 tumor biomarker levels with various cancer diagnoses, obtained from a nation-wide cancer 53 registry, and for comparison, with four non-neoplastic diseases. 54 55 Materials and Methods 56 Cancer diagnoses, including the date of diagnosis, were extracted from the Icelandic cancer 57 registry (ICR) (http://www.cancerregistry.is), which contains all diagnoses of solid cancers made 58 in in the country from January 1st 1955 to December 31st 2015 [13]. We also assessed four 59 other diseases; inflammatory bowel disease (IBD), liver cirrhosis and pancreatitis, because 60 these diseases are associated with inflammation in the gastrointestinal organs and 61 fibromyalgia, because patients present with diverse
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