Albright et al. BMC Cancer 2012, 12:138 http://www.biomedcentral.com/1471-2407/12/138 Table 2 Cancer Incidence Rate Ratio: US/Utah rate ratio for US without Utah/Utah, by site, for males and females, 1995-2004, for those cancer sites with significantly higher, or significantly lower rates in Utah than the US Liver and intrahepatic bile duct All Cancer Sites Oral cavity and Pharynx Esophagus Stomach Colon and Rectum Anus Pancreas Larynx Lung and Bronchus Melanoma (skin) Female breast Cervix uteri Corpus and uterus, NOS Ovary Prostate Testis Urinary bladder Kidney and renal pelvis Brain and other nervous system Thyroid Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Myeloma Leukemia Utah Lower 1.20 (1.19, 1.21) 1.31 (1.24, 1.39) 1.66 (1.51, 1.82) 1.51 (1.41, 1.62) 1.31 (1.27, 1.34) 1.23 (1.06, 1.44) 1.89 (1.72, 2.07) 1.32 (1.25, 1.40) 2.01 (1.80, 2.26) 1.17 (1.14, 1.19) 1.24 (1.15, 1.35) 1.08 (1.03, 1.13) 1.07 (1.01, 1.14) 1.25 (1.21, 1.30) 1.33 (1.26, 1.40) 1.22 (1.11, 1.35) 1.07 (1.03, 1.11) 1.09 (1.02, 1.17) 1.07 (1.03, 1.13) Utah Higher 0.86 (0.83, 0.89) 0.95 (0.94, 0.97) 0.86 (0.79, 0.93) 0.94 (0.89, 0.99) 0.82 (0.78, 0.86) Rates are per 100,000 and age-adjusted to the 2000 US Standard population (19 age groups - Census p 25-1130) standard; Confidence intervals are 95% for rates and ratios [22,23]. be analyzed (with respect to the amount of ancestral genealogy data available) sample sizes have still increased substantially from the 1994 analysis e.g., pros- tate cancer increased from 8,060 cases in 1994 to 13,933 cases in this study. Nine cancer sites previously not ana- lyzed due to inadequate sample size in 1994 are pre- sented here for the first time. These newly analyzed cancer sites include: larynx (n = 427), female genitals (n = 365), anus (n = 396), tongue (n = 347), pharynx (n = 315), oropharynx (n = 261), salivary (n = 338), esopha- gus (n = 520), and bone cancers (n = 294). Results of the GIF test, shown in Table 3 include the cancer site, the number of cases, the overall case average relatedness (case GIF), the average relatedness of con- trols (mean control GIF), the overall average distant relatedness (case dGIF), the average distant relatedness of controls (mean control dGIF), the standard deviation of the control GIF (SD Control GIF), and the standard deviation of the control dGIF (SD Control dGIF), the Page 4 of 7 empirical significance for overall excess of relatedness, and the empirical significance for the distant relatedness (dGIF) statistic. The empirical significance for the GIF test of overall familial clustering (both close and distant) is the same algorithm used to calculate the GIF in pre- viously published reports on the familiality of cancer in Utah [3,4]. The GIF values for both cases and controls are higher now than in previous publications for two reasons, we are analyzing more recent birth cohorts and we are only considering those individuals with specific ancestral genealogy requirements. Distant genealogical index of familiality results We also present, for the first time for cancer, our expansion of the GIF test to include a test for excess distant relatedness (dGIF). The case, control dGIF statis- tics, and the empirical significance for the dGIF test are shown for all cancer sites in Table 3. This analysis iden- tifies 6 cancer sites for which a significant excess relat- edness is observed in distant relationships (p < 0.0013, corrected), strongly supporting a genetic contribution to cancer predisposition. These 6 cancers include some with well known genetic effects and already identified predisposition genes, as well as some for which a genetic hypothesis has not yet been made. The 6 sites include chronic lymphocytic leukemia, thyroid, lip, lung, pros- tate, and melanoma. We note that some cancers with already identified predisposition genes (e.g. breast cancer, colon cancer) did show significant evidence for excess relatedness, but did not show significant excess familiality under the dGIF test. Multiple gene identifications of subsets of breast and colon cancers have provided clear evidence of a genetic contribution to some portion of these two cancer sites (considered independently), but it is noted that the percent of familial cases explained by the known predisposition genes is low, and that the known predisposition genes primarily explain dense pedigrees with close relatives. It therefore may not be a surprise that the dGIF test shows borderline significance for colon cancer and is not significant for breast cancer. We consider the dGIF a conservative test for this rea- son. Those cancers identified to have a significant dGIF test represent those cancers with the most significant evidence for a genetic predisposition, exhibiting excess risk in distant, as well as in close relatives. However, the dGIF test is not the only indication for a genetic contri- bution to predisposition. Typically, when analyzing a single cancer site, we use both Relative Risk estimates and GIF tests to more completely test the hypothesis of a genetic contribution. Similar to previously published GIF analyses [8,12], we observed a significant excess of relatedness of cases for most cancers studied. Before correction for multiple