Scientific Highlights

BILIARY TRACT CANCER

Gene Variants

The authors evaluated 62 single nucleotide polymorphisms (SNPs) in 22 inflammation-related genes in relation to biliary tract cancer and gallstones in a population-based case-control study conducted in Shanghai, China. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls. Fourteen SNPs were related to the risk of biliary cancer and stones. Variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Among the 10 genes with multiple SNPs from which haplotypes were inferred, only 1 IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer and biliary stones, relative to the most frequent haplotype. Common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for studies on the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer. (Hsing AW, Sakoda LC, Rashid A, Andreotti G, Chen J, Wang BS, Shen MC, Chen BE, Rosenberg PS, Zhang M, Niwa S, Chu L, Welch R, Yeager M, Fraumeni JF Jr, Gao YT, Chanock SJ. Variants in inflammation genes and the risk of biliary tract cancers and stones: A population-based study in China. Cancer Res 2008;68:6442–6452)

In the same study population, five SNPs in four DNA repair genes (MGMT, RAD23B, CCNH, and XRCC3) were evaluated. MGMT EX5-25C>T (rs12917) was associated with biliary tract cancer. Independent of gallstones, subjects carrying the CT genotype had a significantly reduced risk of gallbladder cancer (odds ratio [OR] = 0.63) and nonsignificantly reduced risks of bile duct (OR = 0.61) and ampulla of Vater (OR = 0.85) cancers. This marker was not associated with biliary stones. Findings suggest that MGMT gene variants may alter susceptibility to biliary tract cancer, particularly gallbladder cancer. (Zhang M, Huang WY, Andreotti G, Gao YT, Rashid A, Chen J, Sakoda LC, Shen MC, Wang BS, Chanock S, Hsing AW. Variants of DNA repair genes and the risk of biliary tract cancers and stones: A population-based study in China. Cancer Epidemiol Biomarkers Prev 2008;17:2123–2127)

Hepatitis B and C Virus Infection

Also in the Shanghai study, the authors examined the relationships of hepatitis B and C virus infection with risks of biliary tract cancer and biliary stones. Hepatitis B surface antigen (HBsAg) seroprevalence was 7.3% among controls and 14.2% among patients with extrahepatic bile duct cancer, resulting in a 2.4-fold risk. No association with HBsAg was found for cancers of the gallbladder or ampulla of Vater or for stones in the gallbladder or bile duct. Prevalence of hepatitis C infection in this population was low (2%), limiting the ability to detect an association with biliary diseases. (Hsing AW, Zhang M, Rashid A, McGlynn KA, Wang BS, Niwa S, Ortiz-Conde BA, Goedert JJ, Fraumeni JF Jr, O’Brien TR, Gao YT. Hepatitis B and C virus infection and the risk of biliary tract cancer: A population-based study in China. Int J Cancer 2008;122:1849–1853)

 

BLADDER CANCER

Urination Frequency

The effect of urination frequency on bladder cancer risk was evaluated in a large, multicenter case-control study, based on interviews conducted with 884 bladder cancer patients and 996 controls in Spain. A consistent, inverse trend in risk with increasing nighttime voiding frequency was observed in both men (p = 0.0003) and women (p = 0.07); voiding at least two times per night was associated with a significant, 40% to 50% risk reduction. The protective effect of nocturia was apparent among study participants with low, moderate, and high water consumption. The risk associated with cigarette smoking was reduced by nocturia. Compared with nonsmokers who did not urinate at night, current smokers who did not urinate at night had an OR of 7.0, whereas those who voided at least twice per night had an OR of 3.3 (p for trend = 0.0005). Findings suggest a strong protective effect of nocturia on bladder cancer risk, providing evidence that bladder cancer risk is related to the contact time of the urothelium with carcinogens in urine. Increased urination frequency, coupled with possible dilution of the urine from increased water intake, may diminish the effect of urinary carcinogens on bladder cancer risk. (Silverman DT, Alguacil J, Rothman N, Real FX, García-Closas M, Cantor KP, Malats N, Tardón A, Serra C, García- Closas R, Carrato A, Lloreta J, Samanic C, Dosemeci M, Kogevinas M. Does increased urination frequency protect against bladder cancer? Int J Cancer 2008;123:1644–1648)

 

BREAST CANCER

Use of SNPs for Risk Prediction

One purpose for seeking common alleles associated with disease is to use them to improve models for projecting individualized disease risk. Two genome-wide association studies (GWAS) and a study of candidate genes recently identified seven common SNPs, located in FGFR2, TNRC9 (TOX3), MAP3K1, LSP1, CASP8, chromosomal region 8q, and chromosomal region 2q35, that were associated with breast cancer risk in independent samples. Estimates of relative risks and allele frequencies from these studies were used to estimate how much these SNPs could improve discriminatory accuracy, measured as the area under the receiver operating characteristic curve (AUC). A model with these 7 SNPs (AUC = 0.574) and a hypothetical model with 14 such SNPs (AUC = 0.604) have less discriminatory accuracy than an existing model, NCI’s Breast Cancer Risk Assessment Tool (BCRAT), which uses age at menarche and first live birth, family history of breast cancer, and history of breast biopsy examinations (AUC = 0.607). Adding the seven SNPs to BCRAT improved discriminatory accuracy to an AUC of 0.632, which was less than the improvement from adding mammographic density. Experience to date and quantitative arguments indicate that a huge increase in the numbers of subjects in GWAS would be required to find enough SNPs to achieve high discriminatory accuracy (see Figure 1). (Gail MH. Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 2008;100:1037–1041)

 

Genetic Variants Associated with Subtypes

The authors investigated whether associations between GWAS-identified SNPs in five loci (FGFR2, TNRC9, MAP3K1, 8q24, and LSP1) and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. Whether the SNPs influenced overall survival in 13,527 cases from 13 studies was also assessed. rs2981582 in FGFR2 was more strongly related to estrogen receptor (ER)– positive (OR [per allele] = 1.31) than ER-negative (OR [per allele] = 1.08) disease (p for heterogeneity = 10^-13). This SNP was also more strongly related to PR-positive, low-grade, and node-positive tumors (p = 10^-5, 10^-8, and 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low-grade tumors (p = 0.001, 0.011, and 10^-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease; the strongest association was for rs3803662 in TNRC9 (OR [per allele] = 1.14). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (hazard ratio [HR] [per allele] = 0.90), which was attenuated and nonsignificant after adjusting for known prognostic factors. Thus, common genetic variants differentially influence subtype-specific risks of breast cancer. Findings support the hypothesis that ER-positive and -negative disease are biologically distinct. (García-Closas M, et al., for the Breast Cancer Association Consortium. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 2008;4:e1000054)

 

COLORECTAL CANCER

Risks Associated with Chromosome 8q24 Variants

The associations of 15 polymorphisms in chromosome 8q24 regions with risk were investigated in a pooled analysis of 2,587 colorectal adenoma cases, 547 colorectal cancer cases, and 2,798 controls from four studies. Three polymorphisms (rs10808555, rs6983267, and rs7837328) were found to be associated with colorectal tumor risk (see Figure 2). The association was strongest for the rs6983267 variant and was similar for adenoma (OR [per allele] = 1.16; p = 0.0002) and cancer (OR [per allele] = 1.17; p = 0.03). The strength of the association of the regional haplotype containing variant alleles at rs10808555, rs6983267, and rs7837328 but not rs10505476 was greater than that of any single variant for adenoma (OR = 1.27; p = 0.0001) and cancer (OR = 1.26; p = 0.03). The risk associated with rs6983267 was stronger for multiple adenomas (OR [per allele] = 1.29; p = 5.6 × 10^-6) than for single adenomas (OR [per allele] = 1.10; p = 0.03; p for heterogeneity = 0.008). (Berndt SI, Potter JD, Hazra A, Yeager M, Thomas G, Makar KW, Welch R, Cross AJ, Huang WY, Schoen RE, Giovannucci E, Chan AT, Chanock SJ, Peters U, Hunter DJ, Hayes RB. Pooled analysis of genetic variation at chromosome 8q24 and colorectal neoplasia risk. Hum Mol Genet 2008;17:2665–2672)

 

ESOPHAGEAL CANCER

Continued Increases in Adenocarcinoma Incidence

Rapid increases in the incidence of adenocarcinoma of the esophagus have been reported among white men. Temporal patterns of this disease by sex, stage, and age were further explored using data from the Surveillance, Epidemiology, and End Results program. A total of 22,759 patients were diagnosed with esophageal cancer between 1975 and 2004, including 9,526 diagnosed with adenocarcinoma. Among white men, increases in the incidence of esophageal cancer were largely attributed to a 463% increase in the incidence of adenocarcinoma over this time period, from 1.01 per 100,000 person-years in 1975 to 1979 to 5.69 in 2000 to 2004. A similar rapid increase was also apparent among white women, among whom the adenocarcinoma rate increased 335%, from 0.17 to 0.74 per 100,000 person-years, over the same time period. Adenocarcinoma rates rose among white men and women in all stage and age groups (see Figure 3). (Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst 2008;100:1184–1187)

 

HIV-RELATED CANCERS

Cancer Risk in HIV-infected Persons

The authors linked HIV/AIDS and cancer registries in three states to study cancer risk among 57,350 HIV-infected persons (initially AIDS-free) registered between 1991 and 2002. Subjects were followed for five years after registration, and 871 cancers occurred. Risk was elevated for Kaposi sarcoma (KS, standardized incidence ratio [SIR] = 1,300), non-Hodgkin lymphoma (NHL, SIR = 7.3), cervical cancer (SIR = 2.9), and several non–AIDS-defining malignancies, including Hodgkin lymphoma (SIR = 5.6) and cancers of the lung (SIR = 2.6) and liver (SIR = 2.7). KS and NHL incidence declined over time but remained elevated in 1996 to 2002. Incidence increased in 1996 to 2002 compared with 1991 to 1995 for Hodgkin lymphoma (relative risk [RR] = 2.7) and liver cancer (RR = infinite). Non–AIDS-defining cancers comprised 31.4% of cancers in 1991 to 1995 vs. 58.0% in 1996 to 2002. For KS and NHL, risk was inversely related to CD4 count, but these associations attenuated after 1996. Thus, KS and NHL incidence declined markedly in recent years, likely reflecting highly active antiretroviral therapy (HAART)-related improvements in immunity, whereas incidence of some non–AIDS-defining cancers increased, resulting in a shift in the spectrum of cancer among HIV-infected persons. (Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, Grigg R, Hylton T, Pawlish KS, McNeel TS, Goedert JJ. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008;123:187–194)

Conjunctival Squamous Cell Carcinoma in Persons with AIDS

Squamous cell carcinoma of the conjunctiva (SCCC) has been associated with HIV infection in equatorial Africa. The authors assessed the risk for SCCC and other eye cancers in the updated U.S. HIV/AIDS Cancer Match Study. Based on a study of 491,048 adults with AIDS, SIRs were elevated for SCCC (n = 15; SIR = 12.2), primary ocular lymphoma (n = 35; SIR = 21.7), and ocular KS (n = 17; SIR = 109). Risk for SCCC was elevated regardless of HIV acquisition category, CD4 lymphocyte count, or time relative to AIDS onset. The proportions of eye cancers that were SCCC were highest with greater age, Hispanic ethnicity, and residence in regions with high solar ultraviolet radiation. (Guech- Ongey M, Engels EA, Goedert JJ, Biggar RJ, Mbulaiteye SM. Elevated risk for squamous cell carcinoma of the conjunctiva among adults with AIDS in the United States. Int J Cancer 2008;122:2590–2593)

 

KIDNEY CANCER

Role of Body Size and Physical Activity

The relationship between body mass index (BMI) and invasive renal cell carcinoma (RCC) was analyzed in the NIH-AARP Diet and Health Study, a large, prospective cohort of participants aged 50 to 71 years at baseline in 1995 to 1996, with follow-up through 2003. Detailed analyses were conducted in a subcohort assessing BMI at younger ages (18, 35, and 50 years), weight change across three consecutive age intervals, waist and hip size as well as waist-tohip ratio, and height at age 18. Among 1,022 male and 344 female cases, RCC was strongly related to BMI at study baseline. Among subjects analyzed in the subcohort, RCC associations were strongest for baseline BMI and recalled BMI at age 50 and were successively attenuated for recalled BMI at ages 35 and 18. Weight gain in early (18–35 years of age) and mid-adulthood (35–50 years of age) was strongly associated with RCC, whereas weight gain after midlife (age 50 years to baseline) was unrelated. RCC was positively associated with waist-to-hip ratio in women and with height at age 18 in men and women. (Adams KF, Leitzmann MF, Albanes D, Kipnis V, Moore SC, Schatzkin A, Chow WH. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol 2008;168:268–277)

In a related study, the authors examined physical activity in relation to renal cell carcinoma among 482,386 participants who reported their frequency of exercise of at least 20 minutes’ duration, intensity of daily activity, and frequency of physical activity during adolescence. During follow-up, 1,238 cases of renal cell cancer were ascertained. Current exercise, routine physical activity, and activity during adolescence were associated with reduced risk. (Moore SC, Chow WH, Schatzkin A, Adams KF, Park Y, Ballard-Barbash R, Hollenbeck A, Leitzmann MF. Physical activity during adulthood and adolescence in relation to renal cell cancer. Am J Epidemiol 2008;168:149–157)

 

LUNG CANCER

Pathway-based Candidate Gene Evaluation

A pathway-based candidate gene evaluation was conducted to identify genetic variations that may be associated with lung cancer in a population-based case-control study in Xuan Wei, China (122 cases and 111 controls). A total of 1,260 SNPs in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of 10 pathways based on gene ontology. The cell cycle pathway was found to be the most important pathway, with four genes significantly associated with lung cancer, after adjusting for multiple comparisons. Most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival and may be important in lung cancer etiology in Xuan Wei. (Hosgood HD III, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, He X, Chatterjee N, Caporaso N, Zhu Y, Chanock S, Zheng T, Lan Q. Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway. Carcinogenesis 2008;29:1938-1943)

Gender, Smoking, and Lung Cancer Risk

To address whether women are more susceptible than men to lung cancer caused by cigarette smoking, incidence rates of lung cancer by strata of smoking use were compared in men and women in the NIH-AARP cohort. A total of 279,214 men and 184,623 women aged 50 to 71 years at study baseline were included in this analysis, with lung cancers occurring among 4,097 men and 2,237 women. Incidence rates were 20.3 per 100,000 person-years in men who had never smoked (99 cancers) and 25.3 in women who had never smoked (152 cancers; HR = 1.3 for women compared with men). The incidence rate among current smokers who smoked more than two packs per day was 1,259.2 in men and 1,308.9 in women. In current smokers, in a model adjusted for typical smoking dose, the HR was 0.9 for women compared with men. In former smokers, in a model adjusted for years of cessation and typical smoking dose, the HR was 0.9 for women compared with men. Incidence rates of adenocarcinoma, small-cell carcinoma, and undifferentiated tumors were similar in men and women, but rates of squamous tumors in men were somewhat higher than those in women. Findings suggest that women are not more susceptible than men to the carcinogenic effects of cigarette smoking in the lung. In smokers, incidence rates tended to be higher in men than women with comparable smoking histories, but differences were modest. (Freedman ND, Leitzmann MF, Hollenbeck AR, Schatzkin A, Abnet CC. Cigarette smoking and subsequent risk of lung cancer in men and women: Analysis of a prospective cohort study. Lancet Oncol 2008;9:649–656)

 

LYMPHOMA

Lymphoproliferative Disorders in Relatives

To quantify relative risks of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and other lymphoproliferative disorders in first-degree relatives of LPL/WM patients, the authors identified 2,144 LPL/WM patients (1,539 WM and 605 LPL) diagnosed in Sweden, 8,279 population-based matched controls, and linkable first-degree relatives of patients (n = 6,177) and controls (n = 24,609). First-degree relatives of LPL/WM patients were found to have 20-fold, 3-fold, 3.4-fold, and 5-fold increased risks of LPL/WM, NHL, chronic lymphocytic leukemia (CLL), and monoclonal gammopathy of undetermined significance (MGUS), respectively, whereas there was no evidence of an increased risk of developing multiple myeloma or Hodgkin lymphoma. In analyses stratified by type of first-degree relative (parent, sibling, or offspring), age at diagnosis of the probands (above or below 70 years), and sex of the first-degree relative, the risk estimates were not significantly different from the overall analyses. Findings of highly increased risks of developing LPL/WM, NHL, CLL, and MGUS support the operation of shared susceptibility genes that predispose to LPL/WM and other lymphoproliferative disorders. (Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia patients: A population-based study in Sweden. Blood 2008;112:3052–3056)

 

MYELOPROLIFERATIVE NEOPLASMS

Risks in First-degree Relatives

Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). To quantify risks of various types of MPNs and related malignancies among relatives, the authors identified 6,217 PV, 2,838 ET, 1,172 MF, and 812 MPN not otherwise specified (NOS) patients diagnosed in Sweden; 43,550 controls; and first-degree relatives of cases (n = 24,577) and controls (n = 99,542). Relatives of MPN patients had significantly increased risks of PV (relative risk [RR] = 5.7), ET (RR = 7.4), and MPN NOS (RR = 7.5). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings compatible with a model of recessive genetic inheritance. Mean age at MPN diagnosis was not different for affected relatives of cases (57.5 years) vs. controls (60.6 years), and risk of MPN by age was not different for parents vs. offspring of MPN cases. Relatives of MPN patients also had a borderline increased risk of chronic myeloid leukemia (RR = 1.9; p = 0.09). Findings among first-degree relatives of MPN patients support the hypothesis that there are common, strong, shared susceptibility genes. (Landgren O, Goldin LR, Kristinsson SY, Helgadottir EA, Samuelsson J, Björkholm M. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 2008;112:2199–2204)

 

PROSTATE CANCER

Risk Associated with Serum Vitamin D Levels

The association between serum 25-hydroxyvitamin D (25[OH]D) level and risk of prostate cancer was investigated in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The study included 749 patients with incident prostate cancer diagnosed one to eight years after blood draw and 781 matched controls. All study participants were selected from the trial screening arm, which included annual standardized prostate cancer screening. No significant trend in overall prostate cancer risk was observed with increasing season-standardized serum 25(OH)D level. However, serum 25(OH)D concentrations greater than the lowest quintile (Q1) were associated with increased risk of aggressive (Gleason sum ≥ 7 or clinical stage III or IV) disease (in a model adjusting for matching factors, study center, and history of diabetes, ORs for Q2 vs. Q1 = 1.20, for Q3 vs. Q1 =1.96, for Q4 vs. Q1 = 1.61, and for Q5 vs. Q1 = 1.37; p for trend = 0.05). The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)D were 406, 479, 780, 633, and 544 per 100,000 person-years. In exploratory analyses, these associations with aggressive disease were consistent across subgroups defined by age, family history of prostate cancer, diabetes, BMI, vigorous physical activity, calcium intake, study center, season of blood collection, and assay batch. The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. (Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, Horst RL, Hollis BW, Huang WY, Shikany JM, Hayes RB; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Project Team. Serum vitamin D concentration and prostate cancer risk: A nested case-control study. J Natl Cancer Inst 2008:100:796–804)

 

TESTICULAR CANCER

Insulin-like Growth Factor and Binding Protein Levels

The authors examined associations between testicular germ-cell tumor risk and circulating concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor–binding protein 3 (IGFBP-3) among 517 cases and 790 controls from the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) Study. Overall, there were no associations between IGF-1 or IGFBP-3 concentrations and risk of testicular germ-cell tumors; however, when cases were separated by histologic type, there was a suggestion of a reduction in seminoma risk associated with the highest concentrations of IGF-1 compared with the lowest concentrations (OR = 0.66), contrary to expectation. (Chia VM, Quraishi SM, Graubard BI, Rubertone MV, Erickson RL, Stanczyk FZ, McGlynn KA. Insulin-like growth factor 1, insulin-like growth factor–binding protein 3, and testicular germ-cell tumor risk. Am J Epidemiol 2008;167:1438–1445)

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