BACKGROUND: Germline genetic susceptibilities of rare cancers of the esophagus, stomach, small intestine, testis, (nonmedullary) thyroid gland and bone with high familial risks are not well known. Here, we use familial risk data from the Swedish Family-Cancer Database which contains records of cancers in Swedish families obtained over a century. We compare familial risks for offspring diagnosed with any of these cancers when their parent had or had not that cancer. We review the global literature of the reported constitutional variants that may explain part of the familial risk. MAIN BODY: Familial risks for esophageal and stomach cancers are about 2.0 and apart from early-onset stomach cancer few high-risk variants are known. Genetic studies may be hampered by dominant environmental risk factors for these cancers. Small intestinal carcinoids have a very high familial risk (28 between siblings) but no high-risk genes have been identified to explain this. Low-risk polygenic variants have been identified. Small intestinal adenocarcinoma is a manifestation in Lynch syndrome. Testicular and thyroid cancers are characterized by high familial risk (about 5) which may be explained largely by a polygenic background, although thyroid cancer is a component in a number of rare cancer syndromes. Several predisposing genes have been identified for bone cancer (familial risk 7). CONCLUSIONS: The discussed cancers are rare and they present with a relatively high familial risk, in spite of lacking identified high-penetrant constitutional variants. It is possible that the polygenic component, already recognized for testis cancer, is stronger than previously expected. Thus polygenic models with rare high/moderate- and low-risk variants could fit the familial risk and shape the germline genetic landscape of these cancers. Polygenic background may have clinical implications.

Biomedical Center Faculty of Medicine Charles University Pilsen 30605 Czech Republic

Cancer Gene Therapy Group Translational Immunology Research Program University of Helsinki Helsinki Finland

Comprehensive Cancer Center Helsinki University Hospital Helsinki Finland

Department of Otorhinolaryngology Head and Neck Surgery Helsinki University Hospital and University of Helsinki Helsinki Finland

Department of Urology Helsinki University Hospital Helsinki Finland

Division of Cancer Epidemiology German Cancer Research Center Im Neuenheimer Feld 580 D 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Skin and Allergy Hospital Helsinki University Hospital and University of Helsinki Helsinki Finland

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