title: Location of metastases in cancer of unknown primary are not random and signal familial clustering.
abstract: Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. 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' esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative's 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).
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Center for Primary Health Care Research, Lund University, Sweden.|Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sundquist
authors.affiliation: Center for Primary Health Care Research, Lund University, Sweden.|Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Sundquist
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.|Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.affiliation: Center for Primary Health Care Research, Lund University, Sweden.
authors.forename: Jianguang
authors.initials: J
authors.lastname: Ji
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology*; D009382:Neoplasms, Unknown Primary / Q000453:epidemiology* / Q000473:pathology*; D013548:Sweden / Q000453:epidemiology