BackgroundThe contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.Methods and FindingsWe have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland.We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.ConclusionWe conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.
Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.
Background. Chordomas are lobulated neoplasms composed of physaliphorous cells and their precursors; some have atypical, epithelioid, or spindle cell features. Fewer than one‐sixth of chordomas arise in the mobile (cervical, thoracic, or lumbar) spine. Forty‐eight percent originate in the sacrococcygeal region and 39% in the sphenoocciput. Methods. The study included 40 patients, 27 men and 13 women (2:1), with chordoma of the mobile spine. Their clinical and histopathologic features are described. Results. Nineteen tumors (48%) were located in the cervical spine, 7 (17%) in the thoracic spine, and 14 (35%) in the lumbar area. Most patients underwent subtotal removal of the tumor and postoperative irradiation. Variations in histologic appearance, including an occasional chondroid background, did not affect biologic behavior. Twenty‐three patients (58%) were alive 5 years after surgery. Eventually, 25 patients (63%) died of tumor. Metastasis developed in two patients (5%). In contrast to some other studies, metastasis was a rare occurrence. Conclusion. Chordoma of the mobile spine is a slow‐growing, recurring neoplasm of low metastatic potential that incapacitates by locally aggressive growth.
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