Scientific Highlights

BREAST CANCER

Age-related Incidence Rate Crossover

Although breast cancer incidence is higher among black than white women under age 40, the reverse is true among older women. To quantify this crossover, data for 440,653 women diagnosed with invasive breast cancer from NCI’s Surveillance, Epidemiology, and End Results (SEER) database from 1975 through 2004 were examined (see Figure 1). Age-specific incidence rates overall (expressed as number of breast cancers per 100,000 woman-years) were higher among black (15.5) than white (13.1) women younger than 40 years and higher among white (281.3) than black (239.5) women aged 40 years or older. The black-to-white incidence rate crossover was observed more so for those with low-risk disease than for those with high-risk disease. In addition, the crossover occurred at earlier ages of diagnosis for low-risk than for high-risk tumor characteristics. (Anderson WF, Rosenberg PS, Menashe I, Mitani A, Pfeiffer RM. Age-related crossover in breast cancer incidence rates between black and white ethnic groups. J Natl Cancer Inst 2008;100:1804–1814)

 

Risk Factors for Male Breast Cancer

In the prospective NIH-AARP Diet and Health Study, breast cancer developed in 121 of 324,920 men studied. Men who reported a first-degree relative with breast cancer had an increased risk of breast cancer (relative risk [RR] = 1.92). Increased risk was also associated with a history of a bone fracture (RR = 2.20), obesity (RR = 1.79 for body mass indices of 30 vs. < 25 kg/m2), and low physical activity, even after adjustment for body mass index. Smokers were at somewhat elevated risk, although trends were inconsistent. Alcohol consumption was not related to risk. The identified risk factors show some commonalities with female breast cancer. Differences may reflect unique mechanisms associated with androgens and their ratio to bioavailable estrogens. (Brinton LA, Richesson DA, Gierach GL, Lacey JV Jr, Park Y, Hollenbeck AR, Schatzkin A. Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst 2008;100:1477–1481)

 

CERVICAL CANCER

Immune and DNA Repair Genes

Host genetic factors possibly related to persistence of human papillomavirus (HPV) infection and progression to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer were examined. The authors genotyped 92 single nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration = 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. A SNP in the Fanconi anemia complementation group A gene (FANCA), G501S, was associated with increased risk of CIN3 or cancer. The AG and GG genotypes had a 1.3-fold and 1.7 fold increased risk for CIN3 and cancer, respectively (p for trend = 0.008; referent, AA). The FANCA haplotype that included G501S also conferred increased risk of CIN3 or cancer, as did a different haplotype that included two other FANCA SNPs (G809A and T266A). A SNP in the innate immune gene IRF3 (S427T) was associated with increased risk of HPV persistence. Results support the role of FANCA variants in cervical cancer susceptibility and IRF3 in HPV persistence. (Wang SS, Bratti MC, Rodríguez AC, Herrero R, Burk RD, Porras C, González P, Sherman ME, Wacholder S, Lan ZE, Schiffman M, Chanock SJ, Hildesheim A. Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J Infect Dis 2009;199:20–30)

 

CHILDHOOD CANCER

Prenatal and Perinatal Risk Factors

Prenatal, perinatal, and neonatal risk factors for neuroblastoma were investigated by linking 245 pediatric cases diagnosed between 1973 and 1995 from the Swedish Cancer Register to five controls per case from the Swedish Medical Birth Register. Increased risks were associated with maternal anemia during pregnancy (odds ratio [OR] = 2.95), neonatal respiratory distress (OR = 3.61), and low one-minute Apgar score (OR = 2.23) among cases diagnosed before one year of age, but not among older cases. (Bluhm E, McNeil DE, Cnattingius S, Gridley G, El Ghormli L, Fraumeni JF Jr. Prenatal and perinatal risk factors for neuroblastoma. Int J Cancer 2008;123:2885–2890)

 

HEMATOPOIETIC MALIGNANCIES

Risks with Viral and Alcoholic Hepatitis

The authors evaluated risks of hematopoietic malignancies by subtype with prevalent hepatitis C virus (HCV), hepatitis B virus (HBV), and alcoholic hepatitis among 61,464 cases (aged ≥ 67) with hematopoietic malignancies and 122,531 population-based controls, frequency matched by gender, age, and year (1993–2002), from the SEER-Medicare database. HCV, HBV, and alcoholic hepatitis were reported in 195 (0.3%), 111 (0.2%), and 404 (0.7%) cases and 264 (0.2%), 242 (0.2%), and 798 (0.7%) controls, respectively. HCV was associated with increased risk of diffuse large B-cell lymphoma (OR = 1.5), Burkitt lymphoma (OR = 5.2), follicular lymphoma (OR = 1.9), marginal zone lymphoma (OR = 2.2), and acute myeloid leukemia (OR = 1.5, CI = 1.0–2.4). In contrast, HBV was unrelated to any hematopoietic malignancies. Alcoholic hepatitis was associated with decreased risk of non-Hodgkin lymphoma (NHL) overall but increased risk of Burkitt lymphoma. HCV may induce lymphoproliferative malignancies through chronic immune stimulation. (Anderson LA, Pfeiffer R, Warren JL, Landgren O, Gadalla S, Berndt SI, Ricker W, Parsons R, Wheeler W, Engels EA. Hematopoietic malignancies associated with viral and alcoholic hepatitis. Cancer Epidemiol Biomarkers Prev 2008;17:3069–3075)

 

LUNG CANCER

Inhaled Arsenic among Copper Smelter Workers

In a study of the relationship between respiratory cancer mortality and cumulative inhaled arsenic exposure in a cohort of copper smelter workers, the association between respiratory cancer and cumulative arsenic exposure was consistent with linearity within categories of arsenic concentration. The slope of the linear relationship with cumulative exposure increased with increasing arsenic concentration category. Results suggest a direct concentration effect from inhaled inorganic arsenic, whereby the excess relative risk for a fixed cumulative exposure was greater when delivered at a higher concentration and shorter duration than when delivered at a lower concentration and longer duration. (Lubin JH, Moore LE, Fraumeni JF Jr, Cantor KP. Respiratory cancer and inhaled inorganic arsenic in copper smelters workers: A linear relationship with cumulative exposure that increases with concentration. Environ Health Perspect 2008;116:1661–1665)

Menstrual and Reproductive Factors in Nonsmokers

The authors examined hormonal factors in relation to lung cancer risk in the prospective Shanghai Women’s Health Study, which recruited Chinese women aged 40 to 70 years from selected urban communities between 1996 and 2000. This analysis included 71,314 women and 220 lung cancer cases who were lifetime nonsmokers and had no history of cancer at baseline. Later age at menopause (≥ 51 vs. < 46 years; hazard ratio [HR] = 0.63), longer reproductive period (≥ 36 vs. < 31 years; HR = 0.60), higher parity (≥ 4 vs. 0 children; HR = 0.42), and intrauterine device use (HR = 0.59) were associated with decreased risks, suggesting a role for hormonal factors in the etiology of lung cancer among nonsmoking women. (Weiss JM, Lacey JV Jr, Shu XO, Ji BT, Hou L, Yang G, Li H, Rothman N, Blair A, Gao YT, Chow WH, Zheng W. Menstrual and reproductive factors in association with lung cancer in female lifetime nonsmokers. Am J Epidemiol 2008;168:1319–1325)

Changing Risks with Portable Stove Use

Domestic fuel combustion from cooking and heating, to which about 3 billion people worldwide are exposed, is associated with increased lung cancer risk. Lung cancer incidence in Xuanwei is the highest in China, and the attributable risk of lung cancer from unvented smoky coal burning is greater than 90%. To evaluate lung cancer trends after changing from unvented to portable stoves, lifetime smoky coal users in a retrospective cohort of all farmers born between 1917 and 1951 and residing in Xuanwei in 1976 were studied. Of the 42,422 enrolled farmers, 4,054 lifetime smoky coal users changed to portable stoves, 4,364 did not change, and 1,074 died of lung cancer. Portable stoves were associated with decreased risk of lung cancer mortality in men (HR = 0.62) and women (HR = 0.41), providing evidence for a cost-effective intervention that could substantially improve health in developing countries (see Figure 2). (Hosgood HD III, Chapman R, Shen M, Blair A, Chen E, Zheng T, Lee K-M, He X, Lan Q. Portable stove use is associated with lower lung cancer mortality risk in lifetime smoky coal users. Br J Cancer 2008;99:1934–1939)

Risk after Detection of Lung Scarring

A total of 66,863 cancer-free trial participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, aged 55 to 74 years, who received a baseline chest radiograph and were followed up for up to 12 years were included in a study of localized pulmonary scarring and lung cancer risk. Scarring was present on the baseline chest radiograph for 5,041 subjects (7.5%) and was associated with elevated lung cancer risk (809 lung cancer cases; HR = 1.5). This association was specific for cancer in the lung ipsilateral to the scar (HR = 1.8) and absent for contralateral cancer (HR = 0.9). Ipsilateral lung cancer risk was elevated throughout the follow-up period (interval-specific HRs = 1.6, 2.0, 2.1, and 1.7 during 0.01–2, 2.01–4, 4.01–6, and 6.01–12 years after baseline chest radiography, respectively). Findings are consistent with the hypothesis that localized inflammatory processes associated with scarring promote the subsequent development of lung cancer. (Yu YY, Pinsky PF, Caporaso NE, Chatterjee N, Baumgarten M, Langenberg P, Furuno JP, Lan Q, Engels EA. Lung cancer risk following detection of pulmonary scarring by chest radiography in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Arch Intern Med 2008;168:2326–2332)

 

LYMPHOMA

Etiologic Differences among NHL Subtypes

The authors present a comparison of risks for a range of putative risk factors in a population-based case-control study by lymphoma subtype, including diffuse large B-cell (DLBCL; n = 416), follicular (n = 318), and marginal zone lymphomas (n = 106) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 133). Late birth order and high body mass index (≥35 kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. No significant risk factors for follicular lymphoma alone were observed. Data support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/ SLL and follicular lymphoma. (Morton LM, Wang SS, Cozen W, Linet MS, Chatterjee N, Davis S, Severson RK, Colt JS, Vasef MA, Rothman N, Blair A, Bernstein L, Cross AJ, De Roos AJ, Engels EA, Hein DW, Hill DA, Kelemen LE, Lim U, Lynch CF, Schenk M, Wacholder S, Ward MH, Zahm SH, Chanock SJ, Cerhan JR, Hartge P. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes. Blood 2008;112:5150– 5160)

Mitochondrial DNA Copy Number and NHL

Whether higher mitochondrial DNA (mtDNA) copy number in peripheral white blood cell DNA from healthy subjects is associated with later risk of NHL was examined among 104 incident male NHL cases and 104 matched controls within the prospective Alpha-tocopherol, Beta-carotene (ATBC) Cancer Prevention cohort. There was a dose-response relationship between tertiles of mtDNA copy number and risk of NHL (OR = 1.0, 1.4, and 2.4, respectively). The effect was most pronounced for the CLL/SLL subtype (OR = 1.0, 3.2, and 14.1, respectively). (Lan Q, Lim U, Liu CS, Weinstein SJ, Chanock S, Bonner MR, Virtamo J, Albanes D, Rothman N. A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood 2008;112:4247– 4249)

 

METHODS

Combining Family and Case-control Studies

To improve power to detect genetic associations, two approaches were proposed for combining data from a case-control study and a family study that collected families with multiple cases from the same population. In the first approach, a family is viewed as the sampling unit and the joint likelihood is specified for family members using a two-level mixed-effects model to account for random familial effects and residual genetic correlations among family members. The ascertainment of the families is accommodated by conditioning on the ascertainment event. The individuals in the case-control study are treated as families of size one, and their unconditional likelihood is combined with the conditional likelihood for the families. This approach yields subject-specific maximum likelihood estimates of covariate effects. In the second approach, an individual is viewed as the sampling unit. The sampling scheme is accommodated using two-phase sampling techniques, marginal covariate effects are estimated, and correlations among family members are accounted for in the variance calculations. The models are compared in simulations. Data from studies in northeastern Italy on melanoma and a low-risk melanoma susceptibility gene, MC1R, are used to illustrate the approaches. (Pfeiffer RM, Pee D, Landi MT. On combining family and case-control studies. Genet Epidemiol 2008;32:638–646)

Gene-environment Interaction Tests

The authors compare four methods for testing for non-multiplicative gene-environment effects on disease risk in case-control studies: 1) the standard case-control method; 2) the case-only method, requiring an assumption of gene-environment independence; 3) a two-step method that decides between the case-only and case-control estimators depending on a test for the gene-environment independence assumption; and 4) a novel empirical-Bayes (EB) method that combines the case-control and case-only estimators, depending on the sample size and strength of the gene-environment association in the data. The EB procedure, unlike the case-only or two-step methods, can closely maintain a desired type I error under realistic scenarios of gene-environment dependence and yet be more powerful than the traditional case-control analysis when the independence assumption is satisfied at least approximately. Analyses also reveal potential utility of some non-traditional case-control designs that sample controls at a lower rate than the cases. (Mukherjee B, Ahn J, Gruber SB, Rennert G, Moreno V, Chatterjee N. Tests for gene-environment interaction from case-control data: A novel study of type I error, power and designs. Genet Epidemiol 2008;32:615–626)

Urinary Estrogen and Metabolite Measurements

A high-performance liquid chromatography–tandem mass spectrometry method was developed to simultaneously quantitate 15 urinary estrogens and estrogen metabolites (EM): estrone; estradiol; 3 catechol estrogens; 5 estrogens in the 16α pathway, including estriol; and 5 methoxy estrogens. For a reproducibility study, two blinded, randomized aliquots from overnight urines from five follicular and five luteal premenopausal women, five naturally postmenopausal women, and five men were assayed in each of four batches. Data from 25 other participants were added to compare EM levels by menstrual/sex group and assess interindividual variability. For each EM, overall coefficients of variation were 10% or lower. Intraclass correlation coefficients for each menstrual/sex group were generally 98% or higher. Although geometric mean EM concentrations differed among the four groups, rankings were similar, with estriol, 2-hydroxyestrone, estrone, estradiol, and 16-ketoestradiol accounting for 60% to 75% of total urinary EM. Within each group, interindividual differences in absolute concentrations were consistently high; the range was 10- to 100-fold for nearly all EM. The method for measuring 15 urinary EM is highly reproducible, and the range of EM concentrations in each menstrual/sex group is quite large relative to assay variability. (Falk RT, Xu X, Keefer L, Veenstra TD, Ziegler RG. A liquid chromatography-mass spectrometry method for the simultaneous measurement of 15 urinary estrogens and estrogen metabolites: Assay reproducibility and interindividual variability. Cancer Epidemiol Biomarkers Prev 2008;17:3411–3418)

 

PANCREATIC CANCER

Role of Adiponectin Concentrations

The authors conducted a nested case-control study in the ATBC Cancer Prevention Study cohort of male Finnish smokers aged 50 to 69 years at baseline to test whether prediagnostic adiponectin concentrations are associated with pancreatic cancer. Among 311 exocrine pancreatic cancer cases diagnosed between January 1985 and October 2004 and 510 controls, higher adiponectin concentrations were inversely associated with pancreatic cancer (for highest [> 9.8 μ/ml] vs. lowest quintile [≤ 4.6 μ/ml], OR = 0.65; p for trend = 0.04). The inverse association was significant among cases diagnosed five or more years after blood collection (n = 238; for highest vs. lowest quintile, OR = 0.55). (Stolzenberg-Solomon RZ, Weinstein S, Pollak M, Tao Y, Taylor PR, Virtamo J, Albanes D. Prediagnostic adiponectin concentrations and pancreatic cancer risk in male smokers. Am J Epidemiol 2008;168:1047–1055)

 

PROSTATE AND COLON CANCER

Resequencing a Region of Chromosome 8q24

At least three regions of chromosome 8q24 have been independently associated with prostate cancer risk. Haplotypes in two contiguous but independent loci, marked by rs6983267 and rs1447295, were identified in the Cancer Genetic Markers of Susceptibility project (http:// cgems.cancer.gov), which genotyped more than 5,000 prostate cancer cases and controls of European origin. The rs6983267 locus is also strongly associated with colorectal cancer. To ascertain a comprehensive catalog of common SNPs across the two regions, the authors conducted a resequence analysis of 136 kb (chr8: 128,473,000–128,609,802) using the Roche/454 next-generation sequencing technology in 39 prostate cancer cases and 40 controls of European origin. They characterized a comprehensive catalog of common SNPs within this region, including 442 novel SNPs, and have determined the pattern of linkage disequilibrium. Results should be useful for choosing SNPs for fine mapping of association signals in 8q24 and investigations of the functional consequences of select common variants. (Yeager M, Xiao N, Hayes RB, Bouffard P, Desany B, Burdett L, Orr N, Matthews C, Qi L, Crenshaw A, Markovic Z, Fredrikson KM, Jacobs KB, Amundadottir L, Jarvie TP, Hunter DJ, Hoover R, Thomas G, Harkins TT, Chanock SJ. Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers. Hum Genet 2008;124:161–170)

 

RADIATION

Chromosome Translocations in Technologists

Radiologic technologists were surveyed to determine whether their personal cumulative exposure to diagnostic x-rays was associated with increased frequencies of chromosome translocations, an established radiation biomarker possibly suggesting increased cancer risk. Within a large cohort of U.S. radiologic technologists, 150 provided a blood sample for whole-chromosome painting and were interviewed about past x-ray examinations. The number and types of examinations reported were converted to a red bone marrow (RBM) dose score with units that approximated 1 mGy. The estimated mean cumulative RBM radiation dose score was 49 (range = 0–303). After adjustment for age, translocation frequencies significantly increased with increasing RBM dose score with an estimate of 0.004 translocations per 100 cell equivalents per score unit (see Figure 3). The slope estimate was consistent with expectations based on cytogenetic experience and atomic bomb survivor data. (Sigurdson AJ, Bhatti P, Preston DL, Doody MM, Kampa D, Alexander BH, Petibone D, Yong LC, Edwards AA, Ron E, Tucker JD. Routine diagnostic X-ray examinations and increased frequency of chromosome translocations among U.S. radiologic technologists. Cancer Res 2008;68:8825–8831)

 

SMALL INTESTINAL CANCER

Dietary and Factors

Meat and fat intakes were investigated in relation to small intestinal cancer among a half million men and women enrolled in the NIH-AARP Diet and Health Study. During up to eight years of follow-up, 60 adenocarcinomas and 80 carcinoid tumors of the small intestine were diagnosed. Despite slightly elevated HRs for red meat, there were no clear associations for red or processed meat intake with either adenocarcinoma or carcinoid tumors of the small intestine. In contrast, the authors noted a markedly elevated risk for carcinoid tumors of the small intestine with saturated fat intake in both categorical (highest vs. lowest tertile: HR = 3.18) and continuous data (HR = 3.72 for each 10-g increase in intake per 1,000 kcal). Positive associations for meat intake reported in previous case-control studies may be partly explained by saturated fat intake. (Cross AJ, Leitzmann MF, Subar AF, Thompson FE, Hollenbeck AR, Schatzkin A. A prospective study of meat and fat intake in relation to small intestinal cancer. Cancer Res 2008;68:9274–9279)

 

TESTICULAR CANCER

Microlithiasis in Familial Cases and Relatives

A total of 48 men affected with familial testicular germ cell tumors (FTGCT) and 33 unaffected men from 31 families with at least two testicular cancer cases underwent testicular ultrasound (see Figure 4). Testicular microlithiasis (TM) was more prevalent among FTGCT family members than described previously in the general population and was more frequent in the contralateral testicles of affected men than unaffected men (48% vs. 24%). The association appeared stronger for classic TM (≥ 5 microliths, 21% vs. 9%) than for limited TM (< 5 microliths, 27% vs. 15%). TM was bilateral in six of seven (87%) unaffected men. Among affected men, TM was not associated with histology, age at diagnosis, or cancer treatment. Of the 31 families, 10 accounted for a majority (61%) of the TM cases identified (p = 0.11). Findings suggest both a familial predisposition to TM and an association between TM and FTGCT. (Korde LA, Premkumar A, Mueller C, Rosenberg P, Soho C, Bratslavsky G, Greene MH. Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives. Br J Cancer 2008;99:1748–1753)

 

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