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Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives\u2019 esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative\u2019s cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds).<\/jats:p>","DOI":"10.1038\/srep22891","type":"journal-article","created":{"date-parts":[[2016,3,9]],"date-time":"2016-03-09T10:12:05Z","timestamp":1457518325000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Location of metastases in cancer of unknown primary are not random and signal familial clustering"],"prefix":"10.1038","volume":"6","author":[{"given":"Kari","family":"Hemminki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Sundquist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Sundquist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akseli","family":"Hemminki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianguang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,3,9]]},"reference":[{"key":"BFsrep22891_CR1","unstructured":"Greco, F. & Hainsworth, J. Cancer of unknown primary site. In Cancer: Principles and Practice of Oncology (eds DeVita, V. J., Hellman, S., Rosenberg, s. ). Lippincott (2011)."},{"key":"BFsrep22891_CR2","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1200\/JCO.2010.31.5614","volume":"29","author":"K Hemminki","year":"2011","unstructured":"Hemminki, K., Ji, J., Sundquist, J. & Shu, X. Familial risks in cancer of unknown primary: tracking the primary sites. J Clin Oncol 29, 435\u2013440 (2011).","journal-title":"J Clin Oncol"},{"key":"BFsrep22891_CR3","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1016\/S0140-6736(11)61178-1","volume":"379","author":"N Pavlidis","year":"2012","unstructured":"Pavlidis, N. & Pentheroudakis, G. Cancer of unknown primary site. 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J Natl Cancer Inst 105, 782\u2013790 (2013).","journal-title":"J Natl Cancer Inst"},{"key":"BFsrep22891_CR6","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1200\/JCO.2012.43.3755","volume":"31","author":"JD Hainsworth","year":"2013","unstructured":"Hainsworth, J. D. et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol 31, 217\u2013223 (2013).","journal-title":"J Clin Oncol"},{"key":"BFsrep22891_CR7","doi-asserted-by":"publisher","first-page":"x271","DOI":"10.1093\/annonc\/mds357","volume":"23","author":"KA Oien","year":"2012","unstructured":"Oien, K. A. & Dennis, J. L. Diagnostic work-up of carcinoma of unknown primary: from immunohistochemistry to molecular profiling. 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A.H. is shareholder in Oncos Therapeutics, Ltd. A.H. is employee and shareholder in TILT Biotherapeutics Ltd.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22891"}}