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Discovering the causes of cancer and the means of prevention

Scientific Highlights

Summaries of Recently Published DCEG Papers

March 2013 - Linkage Newsletter

Topics

All Cancers

Chronic Fatigue Syndrome and Cancer Incidence

The authors examined the association between chronic fatigue syndrome (CFS) and cancer using data from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare registry. Among approximately 1.2 million cancer cases and 100,000 controls, CFS was present in 0.5% of cancer cases overall and 0.5% of controls. CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL) (odds ratio (OR) = 1.29). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR = 1.34), marginal zone lymphoma (OR = 1.88), and B-cell NHL not otherwise specified (OR = 1.51). Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL. (Chang CM, Warren JL, Engels EA. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer 2012;118:5929–5936)

Clonal Mosaicism, Aging, and Cancer

The authors detected clonal mosaicism, the occurrence of two or more cell lines with different genetic or chromosomal constitutions within a single individual or tissue, for large chromosomal anomalies (duplications, deletions, and uniparental disomy) using single nucleotide polymorphism (SNP) microarray data from more than 50,000 subjects recruited for genome-wide association studies (GWAS). The frequency of detectable clonal mosaicism in peripheral blood is low (0.5%) from birth until 50 years of age, after which it rapidly rises to 2%–3% in older adults. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Subjects with detectable clonal mosaicism had an estimated 10-fold higher risk of a subsequent hematological cancer. (Laurie CC, Laurie CA, Rice K, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012;44:642–650)

Oral Bisphosphonate Use and Cancer Incidence

Recently, oral bisphosphonate use has increased markedly. A few studies have observed associations between bisphosphonates and the risk of breast, colorectal, and esophageal cancer. The authors examined the risk of cancer among 41,826 individuals taking bisphosphonates and a matched control cohort using data from the United Kingdom General Practice Research Database. Compared to the control cohort, bisphosphonate users had reduced risks for all cancer (hazard ratio (HR) = 0.87) and for cancers of the breast (HR = 0.71) and colorectum (HR = 0.74). The findings indicate that bisphosphonates do not appear to increase cancer risk. The extent to which the reductions in breast and colorectal cancer incidence are due to confounding by low bone density is unclear. (Cardwell CR, Abnet CC, Veal P, et al. Exposure to oral bisphosphonates and risk of cancer. Int J Cancer 2012;131:E717–725)

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All-Cause Mortality

Physical Activity and Mortality

To determine the years of life gained after age 40 associated with various levels of leisure time physical activity, the authors examined data from six prospective cohort studies in the NCI Cohort Consortium, comprising 654,827 individuals (82,465 deaths), aged 21–90 years. A physical activity level of 0.1–3.74 metabolic equivalent hours per week (MET-h/wk), equivalent to brisk walking for up to 75 minutes/week, was associated with a gain of 1.8 years in life expectancy relative to no leisure time activity. Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 years at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains also were observed in each body mass index (BMI) group. Being active (7.5+ MET-h/wk) and normal weight (BMI 18.5–24.9) was associated with a gain of 7.2 years of life compared to being inactive and obese (BMI 35.0+, see Figure 1). More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups. (Moore SC, Patel AV, Matthews CE, et al. Leisure time physical activity of moderate to vigorous intensity and mortality: A large pooled cohort analysis. PLoS Med 2012;9:e1001335)

Years of life expectancy lost after age 40 in relation to joint categories of physical activity and body mass index

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Anal Cancer

HIV and Trends in Anal Cancer Incidence

The authors estimated the impact of the HIV epidemic on trends in anal cancer incidence in the United States using data from the HIV/AIDS Cancer Match Study. During 1980–2005, of the 20,533 estimated anal cancer cases, 1,665 (8.1%) had HIV infections. The proportion of anal cancer cases with HIV infection was the highest during 2001–2005 (females: 1.2%; males: 28.4%). From 1980 to 2005, HIV infection did not have an impact on the trends in anal cancer among females (annual increase 3.3% overall and 3.3% without HIV infection) but had a strong impact on the trends among males (annual increase 3.4% overall and 1.7% without HIV infection) (see Figure 2). (Shiels MS, Pfeiffer RM, Chaturvedi AK, et al. Impact of the HIV epidemic on the incidence rates of anal cancer in the United States. J Natl Cancer Inst 2012;104:1591–1598)

Anal cancer incidence in the general U.S. population with and without HIV-infected anal cancer cases, by age and sex, between 1980 and 2005. Corresponding author is Meredith S. Shiels - email shielsms@mail.nih.gov

HPV and Anal Cancer Among HIV-infected Men

The authors evaluated biomarkers for human papillomavirus (HPV)-related anal disease in a cross-sectional screening study that included 363 men followed at an HIV/AIDS clinic. All men had anal cytology samples taken and were evaluated using high-resolution anoscopy and anal biopsies. Using a composite end point of biopsy results and cytology, the authors compared the performance of HPV DNA testing, HPV 16/18 genotyping, HPVE6/E7 mRNA expression, and p16/Ki-67 cytology to detect high-grade anal intraepithelial neoplasias (AINs). A significant trend of increasing percentage of men testing positive with increasing severity of disease was found for all biomarkers analyzed. HPV DNA testing had the highest sensitivity for AIN grade 2 and AIN grade 3 (AIN3), followed by p16/Ki-67, HPV E6/E7 mRNA testing, and HPV 16/18 genotyping. The highest Youden’s index (sensitivity + specificity – 1) was observed for HPV E6/E7 mRNA testing, followed by HPV 16/18 genotyping, p16/Ki-67 cytology, and HPV DNA testing. Increasing the threshold for positivity of p16/Ki-67 to five or more positive cells led to higher specificity but did not change sensitivity for detecting AIN3. The study showed that molecular features of anal disease categories are similar to those of corresponding cervical lesions and that the four biomarkers evaluated for cervical cancer screening may be used for primary anal cancer screening or triage. (Wentzensen N, Follansbee S, Borgonovo S, et al. Human papillomavirus genotyping, human papillomavirus mRNA expression, and p16/Ki-67 cytology to detect anal cancer precursors in HIV-infected MSM. AIDS 2012;26:2185–2192)

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Bladder Cancer

Genetic Selection Marker for Immunotherapy

A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy now being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The authors demonstrated that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies (GWAS) is a strong predictor of PSCA protein expression in bladder tumors. The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. (Kohaar I, Porter-Gill P, Lenz P, et al. Genetic variant as a selection marker for anti-prostate stem cell antigen immunotherapy of bladder cancer. J Natl Cancer Inst 2013;105:69–73)

Pathway Analysis of Genetic Variants

The authors applied a pathway analysis to a bladder cancer genome-wide association study (GWAS) containing data from 3,532 cases and 5,120 controls to evaluate genetic variants collectively with effects that are too small to be detected individually. Using publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome) and additional candidate pathways constructed by the authors, the study included 1,421 pathways, 5,647 genes, and ∼90,000 single nucleotide polymorphisms (SNPs). The researchers used a logistic regression model to assess the marginal trend effect of SNPs on bladder cancer risk. They also used two complementary pathway-based methods (gene-set enrichment analysis, and adapted rank-truncated product) to assess the enrichment of association signals within each pathway. After using the I(2) statistic to minimize false positives, seven pathways (aromatic amine metabolism, nicotinamide adenine dinucleotide (NAD) biosynthesis, NAD salvage, clathrin-derived vesicle budding, lysosome vesicle biogenesis, retrograde neurotrophin signaling, and mitotic metaphase/anaphase transition) remained significant. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). (Menashe I, Figueroa JD, Garcia-Closas M, et al. Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background. PloS One 2012;7:e29396)

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Breast Cancer

Genetic Variant Modifies Risk Among BRCA1/2 Mutation Carriers

The study investigated whether genetic variants in insulin receptor substrate 1 (IRS1) modified ovarian and breast cancer risk in a large cohort of BRCA1 and BRCA2 mutation carriers using samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2. Rs1801278 (Gly972Arg) was associated with ovarian cancer risk among both BRCA1 (hazard ratio (HR) = 1.43) and BRCA2 (HR = 2.21) mutation carriers. For BRCA1 mutation carriers, the breast cancer risk was higher among carriers with class II mutations (HR = 1.86) than among those with class I mutations (HR = 0.86). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR = 2.42). These findings may prove useful for risk prediction for breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers. (Ding YC, McGuffog L, Healey S, et al. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012;21:1362–1370)

Mammographic Density and Breast Cancer Mortality

The investigators evaluated mammographic density in relation to death from breast cancer and all causes within the U.S. Breast Cancer Surveillance Consortium. They studied 9,232 women diagnosed with primary invasive breast carcinoma during the years 1996–2005, with a mean follow-up of 6.6 years. Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS) density classification. A total of 1,795 women died, of whom 889 died of breast cancer. In multivariable analyses adjusted for site, age at and year of diagnosis, cancer stage, body mass index, mode of detection, treatment, and income, high density (BI-RADS 4) was not related to risk of death from breast cancer or death from all causes. Analyses stratified by stage and other prognostic factors yielded similar results, except for an increased risk of breast cancer death among women with low density (BI-RADS 1) who were either obese (hazard ratio (HR) = 2.02) or had tumors of at least 2.0 cm (HR = 1.55). Thus, risk factors for the development of breast cancer may not necessarily be the same as factors influencing the risk of death after breast cancer has developed. (Gierach GL, Ichikawa L, Kerlikowske K, et al. Relationship between mammographic density and breast cancer death in the Breast Cancer Surveillance Consortium. J Natl Cancer Inst 2012;104:1218–1227)

Two Novel Susceptibility Loci from Breast Cancer GWAS

The authors conducted the largest meta-analysis of estrogen receptor negative (ER−) breast cancer to date, comprising 4,754 ER− cases and 31,663 controls from three genome-wide association studies (GWAS): NCI Breast and Prostate Cancer Cohort Consortium, Triple Negative Breast Cancer Consortium, and African American Breast Cancer Consortium. In silico replication of 86 single nucleotide polymorphisms (SNPs) was conducted among an additional 11,209 breast cancer cases (946 with ER− disease) and 16,057 controls of Japanese, Latino, and European ancestry. Two novel loci for breast cancer were identified at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER− breast cancer (combined two-stage odds ratio (OR) = 1.16; p = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08; p = 1.3 × 10−6) and no association with ER+ disease (OR = 1.01; p = 0.67). Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; p = 1.1 × 10−9), and with both ER+ (OR = 1.09; p = 1.5 × 10−5) and ER− (OR = 1.16; p = 2.5 × 10−7) disease. Three known loci associated with ER− (19p13) and both ER− and ER+ breast cancer (6q25 and 12p11) were confirmed. (Siddiq A, Couch FJ, Chen GK, et al. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet 2012;21:5373–5384)

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Cervical Cancer

Genetic Variants and Risk of Persistent HPV Infection

To identify genetic factors that might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV) to persistent HPV infection, and hence to cervical precancer and cancer, the authors assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1,113 genes in 416 cervical intraepithelial neoplasia 3 (CIN 3) cancer cases, 356 women with persistent carcinogenic HPV infection, and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women in the Guanacaste, Costa Rica, HPV natural history cohort. Regions significantly associated with CIN 3 cancer included genes for peroxiredoxin 3 (PRDX3), and ribosomal protein S19 (RPS19). The single most significant single nucleotide polymorphism (SNPs) from each gene associated with CIN 3 cancer were PRDX3 rs7082598 (p for trend < 0.0001) and RPS19 rs2305809 (p for trend = 0.0007). Both SNPs also were associated with progression. (Safaeian M, Hildesheim A, Gonzalez P, et al. Single nucleotide polymorphisms in the PRDX3 and RPS19 and risk of HPV persistence and cervical precancer/cancer. PloS One 2012;7:e33619)

HPV 18, HPV 31, and HPV 45 DNA Methylation and Risk of Cervical Precancer

Following their recent report that the human papillomavirus (HPV) 16 genome was strongly methylated in cervical precancer compared with transient HPV infections, the authors analyzed whole-genome methylation patterns of three other important carcinogenic HPV genotypes: HPV 31, HPV 18, and HPV 45. The authors extracted DNA from cervical cytology specimens from 92 women with precancer and 96 women who were infected with HPV 31, HPV 18, or HPV 45 but who had no cytological or histological abnormalities. After bisulfite modification, the authors performed genome-wide pyrosequencing covering 80–106 sites and calculated differences in median methylation, ORs, areas under the curve, and Spearman rank correlation coefficients for methylation levels at different sites. For all three HPV types, the authors observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia 3 (CIN 3) compared to women with transient infections. The authors also observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve values were 0.81 for HPV 31, 0.85 for HPV 18, and 0.98 for HPV 45. Differential methylation patterns in CIN 3 patients with multiple infections suggest that methylation analysis can clarify which of the infections is causal. The authors concluded that carcinogenic HPV DNA methylation indicates transforming HPV infections and that methylation of carcinogenic HPV types is a general phenomenon that warrants development of diagnostic assays. (Wentzensen N, Sun C, Ghosh A, et al. Methylation of HPV 18, HPV 31, and HPV 45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst 2012;104:1738–1749)

HPV 16 DNA Methylation and Risk of Cervical Precancer

DNA methylation was quantified at 66 CpGs across the human papillomavirus (HPV) genome using serially collected specimens from 92 women with HPV 16 DNA clearance (controls), 72 women with HPV 16 DNA persistence (without cervical intraepithelial neoplasia 2 [CIN 2+]), and 109 women with CIN 2+ from the Guanacaste, Costa Rica, cohort. In diagnostic specimens, 88% of CpG sites had significantly higher methylation levels in CIN 2+ than controls did after correction for multiple tests. The highest area under the receiver operator characteristic curve was 0.82 for CpG site 6457 in L1, and a diagnostic sensitivity of 91% corresponded to a specificity of 60% for CIN 2+. Prospectively, 17% of CpG sites had significantly higher methylation than controls did in pre-diagnostic CIN 2+ specimens. The strongest pre-diagnostic CpG site was 6367 in L1 (area under the curve 0.76). Higher methylation in CIN 2+ cases was not explained by higher viral load. Elevated levels of HPV 16 DNA methylation may be useful to predict concurrently diagnosed and future CIN 2+. (Mirabello L, Schiffman M, Ghosh A, et al. Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 2013;132:1412–1422)

Immunostaining to Improve Cervical Cancer Screening

Human papillomavirus (HPV) DNA testing is highly sensitive and a negative test provides long-term assurance of low cervical cancer risk, but the specificity of HPV DNA testing is limited, requiring better markers for efficient screening. The authors evaluated the performance of p16/Ki-67 in 625 women referred to colposcopy for abnormal cervical cancer screening results. Clinical performance characteristics were calculated for all women stratified by age and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap result. p16/Ki-67 positivity increased with histologic severity—from 26.8% in normal histology to 46.5% in cervical intraepithelial neoplasia 1 (CIN 1), 82.8% in CIN 2, and 92.8% in CIN 3. Among women with CIN 3, p16/Ki-67 positivity increased from 77.8% for women without HPV 16 who were younger than 30 years of age to 100% for women with HPV 16 who were aged 30 years and older. Sensitivity and specificity to detect CIN 3 or greater were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women aged 30 years and older. In women with high-risk HPV-positive atypical squamous cells of undetermined significance and LSIL, sensitivity and specificity for detection of CIN 3 were 90.6% and 48.6%, respectively. The authors found that p16/Ki-67 testing could substantially reduce referral to colposcopy while detecting CIN 3 in women aged 30 years and older with HPV 16. (Wentzensen N, Schwartz L, Zuna RE, et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res 2012;18:4154–4162)

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Gastrointestinal Cancer

HIV/AIDS and Upper Gastrointestinal Cancer

The authors evaluated the risks of histologic and anatomic subtypes of carcinomas and non-Hodgkin lymphomas (NHLs) of the stomach and esophagus in people with AIDS. Using data from the HIV/AIDS Cancer Match Study, which links data collected from 1980 to 2007 for 16 U.S. population-based HIV and AIDS and cancer registries, the authors found that people with AIDS have increased risks of carcinomas of the esophagus (standardized incidence ratio (SIR) = 1.69) and stomach (SIR = 1.44). Risk was increased for esophageal adenocarcinoma (SIR = 1.91) and squamous cell carcinoma (SIR = 1.47). People with AIDS had greater risks than the general population did for carcinomas of the gastric cardia (SIR = 1.36) and noncardia (SIR = 1.53). Although most stomach and esophageal NHLs that developed in people with AIDS were diffuse large B-cell lymphomas, these individuals also had an increased risk of stomach mucosa-associated lymphoid tissue lymphoma (SIR = 5.99). Although rates of NHL decreased from 1980 to 2007, the incidence of carcinomas remained fairly constant over time. (Persson EC, Shiels MS, Dawsey SM, et al. Increased risk of stomach and esophageal malignancies in people with AIDS. Gastroenterology 2012;143:943–950.e2)

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Hepatitis and Hepatocellular Cancer

Hepatocellular Carcinoma Among Persons with AIDS

The authors analyzed population-based registry linkage data from the U.S. HIV/AIDS Cancer Match Study (1980–2009) to examine the risks of hepatocellular cancer (HCC) among individuals with AIDS. Standardized incidence ratios (SIRs) were used to measure HCC risk relative to the general population, and Poisson regression was used to calculate incidence rate ratios (RR) comparing incidence among individuals with AIDS. Among 615,150 individuals with AIDS, HCC risk was almost four times higher than risk in the general population (SIR = 3.8). Although HCC incidence increased steadily across calendar periods, the excess risk in individuals with AIDS compared with the general population remained somewhat constant (SIRs range, 3.5–3.9) between the monotherapy/dual therapy era (1990–1995) and the recent highly active antiretroviral therapy era (2001–2009). In a model adjusted for sex, race/ethnicity, and attained calendar period, HCC incidence increased with advancing age and was associated with HIV risk groups with a known higher prevalence of hepatitis C (adjusted RR = 2.2). HCC incidence in individuals with AIDS has increased over time despite improved HIV treatment regimens, likely reflecting prolonged survival with chronic liver disease. The high incidence in older adults suggests that this cancer will increase in importance with the aging of the HIV-infected population. (Sahasrabuddhe VV, Shiels MS, McGlynn KA, et al. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer 2012;118:6226–6233)

New Interferon Gene Associated with Impaired Clearance of HCV

Chronic infection with hepatitis C (HCV) is a common cause of liver cirrhosis and cancer. The authors performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, they discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590 [ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes (see Figure 3). The findings provide new insights into the genetic regulation of HCV clearance and its clinical management. (Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 [IL28B] creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 2013;45:164–171)

Human liver cells treated to mimic infection with hepatitis C, showing favorable vs unfavorable variants

NSAIDS, Chronic Liver Disease, and Hepatocellular Carcinoma

To investigate the effect of nonsteroidal anti-inflammatory drugs (NSAIDS) on risk of hepatocellular cancer (HCC) and death due to chronic liver disease (CLD), the authors analyzed prospective data on 300,504 men and women in the NIH-AARP Diet and Health Study cohort. The sample included 250 registry-confirmed diagnoses of HCC (n = 250) and 428 other deaths due to CLD. Aspirin users had significantly reduced risks of incidence of HCC (hazard ratio (HR) = 0.59) and mortality due to CLD (HR = 0.55) than people who did not use aspirin. In contrast, users of non-aspirin NSAIDs had reduced risk of mortality due to CLD (HR = 0.74) but not lower risk of incidence of HCC (HR = 1.08) than people who did not use non-aspirin NSAIDs. (Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst 2012;104:1808–1814)

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Leukemia

Genetic Variant in BAK1 Increases Risk of Chronic Lymphocytic Leukemia

The authors performed a meta-analysis of three genome-wide association studies (GWAS) to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of data from 1,121 cases and 3,745 controls. Replication analysis was performed in 861 cases and 2,033 controls. A novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; p = 9.47 × 10−16) was identified. A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. (Slager SL, Skibola CF, Di Bernardo MC, et al. Common variation at 6p21.31 [BAK1] influences the risk of chronic lymphocytic leukemia. Blood 2012;120:843–846)

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Lung Cancer

Genetic Variant in TP63 Increases Risk of Lung Adenocarcinoma

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma; however, this association did not achieve genome-wide significance among never smokers. To determine if this association is independent of tobacco use, the authors genotyped the TP63 single nucleotide polymorphisms (SNPs) reported by a previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma (n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80; 95% confidence interval [CI] = 0.74–0.87). Evidence also showed an association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82; 95% CI = 0.67–0.99). (Hosgood HD 3rd, Wang WC, Hong YC, et al. Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia. Hum Genet 2012;131:1197–1203)

GWAS of Lung Cancer Among Never-smoking Women

The authors conducted a multistage genome-wide association study (GWAS) of lung cancer among Asian women who never smoked. The first stage was based on 5,510 cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. The most promising variants were genotyped in an additional 1,099 cases and 2,913 controls. Three new susceptibility loci at 10q25.2 (rs7086803; p = 3.54 × 10−18), 6q22.2 (rs9387478; p = 4.14 × 10−10) and 6p21.32 (rs2395185; p = 9.51 × 10−9) were identified. The authors also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. They found no evidence of association at 15q25 among never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. (Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 2012;44:1330–1335)

Smoky Coal and Lung Cancer Mortality

The authors conducted a retrospective cohort study comparing mortality from lung cancer between 27,310 lifelong users of “smoky coal” (bituminous) and 9,962 users of “smokeless coal” (anthracite) for household cooking and heating in Xuanwei County, Yunnan Province, China. The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes. Compared with smokeless coal, use of smoky coal was associated with an increased risk of lung cancer death (men: hazard ratio (HR) = 36; women: HR = 99). In Xuanwei, the domestic use of smoky coal is likely to represent one of the strongest effects of environmental pollution reported for cancer risk. (Barone-Adesi F, Chapman RS, Silverman DT, et al. Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study. BMJ 2012;345:e5414)

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Methods

Assessing Risk in GWAS Using Family History

The authors show how to use reports of cancer in family members to discover additional genetic associations or confirm previous findings in genome-wide association studies (GWAS) conducted in case-control, cohort, or cross-sectional studies. The novel family history–based approach allows economical association studies for multiple cancers without genotyping of relatives (as required in family studies), follow-up of participants (as required in cohort studies), or oversampling of specific cancer cases (as required in case-control studies). The performance of the proposed approach is evaluated using data from GWAS previously conducted within the Prostate, Lung, Colon, and Ovarian Cancer (PLCO) Screening Trial. The method may be particularly useful for investigating genetic susceptibility to rare diseases for which accruing cases may be very difficult by using disease information from non-genotyped relatives of participants in multiple case-control and cohort studies designed primarily for other purposes. (Ghosh A, Hartge P, Purdue MP, et al. Assessing disease risk in genome-wide association studies using family history. Epidemiology 2012;23:616–622)

Improving Power when Pooling GWAS of Heterogeneous Traits

Combining genome-wide association studies of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta- or pooled analysis, however, might not be suitable because the studies are often heterogeneous. Individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. The authors propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. The authors present applications and simulation studies to demonstrate that the proposed methods offer improved power and more interpretable results than traditional methods for the analysis of heterogeneous traits. (Bhattacharjee S, Rajaraman P, Jacobs KB, et al. A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits. Am J Hum Genet 2012;90:821–835)

Using Multiple Risk Models to Assess Preventive Interventions

Because many preventive interventions have both adverse and beneficial effects, preventive interventions should be given only to the subset of the population in which the benefits outweigh the risks. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45% but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. To date, recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk alone. The author investigated the extent to which risk models of not only breast cancer but also stroke can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. (Gail MH. Using multiple risk models with preventive interventions. Stat Med 2012;31:2687–2696)

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Ovarian Cancer

Genetic Variant Modifies Risk among BRCA1/2 Mutation Carriers

(See under Breast Cancer)

Menopausal Hormone Therapy and Ovarian Cancer

The investigators evaluated menopausal hormone use and incident ovarian cancer (n = 426) among 92,601 postmenopausal women enrolled in the NIH-AARP Diet and Health Study. Participants were administered questionnaires in 1996–1997 and followed through 2006. Increased risks were associated with long duration use (10 or more years) of unopposed estrogen (relative risk (RR) = 2.15) among women with a hysterectomy and estrogen plus progestin therapy (RR = 1.68) among women with intact uteri (see Figure 4). Similar risks were associated with progestins that were used sequentially (15 days/month; RR = 1.60) or continuously (25 days/month; RR = 1.43). These findings suggest that long duration use of both unopposed estrogens and estrogen plus progestins are associated with increased risks of ovarian cancer and that risk associated with estrogen plus progestin use does not vary by sequential vs. continuous regimen. (Trabert B, Wentzensen N, Yang HP, et al. Ovarian cancer and menopausal hormone therapy in the NIH-AARP Diet and Health Study. Br J Cancer 2012;107:1181–1187)

Association between menopausal hormone therapy and ovarian cancer

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Pancreatic Cancer

Pancreatic Development Genes Related to Pancreatic Cancer

The authors conducted a pathway-based analysis of pancreatic cancer genome-wide association study (GWAS) to identify groups of genes or biological pathways with disease-associated single nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. Using data from 3,851 pancreatic cancer cases and 3,934 controls, 23 biological pathways hypothesized to be relevant to pancreatic cancer were compiled. Associations were found with five pathways: pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response, and apoptosis. After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO, and SHH), the pancreatic development pathway remained significant (p = 8.3 × 10−5), whereas the others did not. The most significant genes in the pancreatic development pathway were NR5A2, HNF1A, HNF4G, and PDX1. (Li D, Duell EJ, Yu K, et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis 2012;33:1384–1390)

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Prostate Cancer

NSAIDS and Prostate Cancer Risk

The authors examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29,450 men in the Prostate, Lung, Colon, and Ovarian Cancer (PLCO) Screening Trial. A total of 3,575 cases of prostate cancer were identified. The hazard ratios (HRs) of prostate cancer associated with less than one pill of aspirin daily and one or more pills of aspirin daily were 0.98 and 0.92, respectively, compared with never using aspirin (p for trend = 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 (HR = 0.87) or men who had a history of cardiovascular-related diseases (HR = 0.89) or arthritis (HR = 0.88). The data did not support an association between ibuprofen use and prostate cancer risk. Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer. (Shebl FM, Sakoda LC, Black A, et al. Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: A PLCO study. Br J Cancer 2012;107:207–214)

Risk of Prostate Cancer and Pesticide Use

Because many studies show elevated risks of prostate cancer among farmers, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study. Based on 1,962 incident cases, including 919 aggressive prostate cancers, among 54,412 applicators, the authors evaluated lifetime use of 48 pesticides. Comparing the highest quartile of exposure to non-exposed, three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos (relative risk (RR) = 1.63; p for trend < 0.001); malathion (RR = 1.43; p for trend = 0.04); and terbufos (RR = 1.29;  p for trend = 0.03). The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer (RR = 1.49; p for trend = 0.02). (Koutros S, Beane Freeman LE, Lubin JH, et al. Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study. Am J Epidemiol 2013;177:59–74.)

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Radiation

Cancer Risks from CT Scans in Childhood

The authors conducted a retrospective cohort study of patients who were first examined with computed tomography (CT) scans in Great Britain between 1985 and 2002, when the patients were younger than 22 years of age. The authors obtained data for cancer incidence, mortality, and loss to follow-up from 1985 through 2008 and estimated absorbed brain and red bone marrow doses per CT scan. To avoid inclusion of scans related to cancer diagnosis, follow-up for leukemia began two years after the first CT and for brain tumors five years after the first CT. During follow-up, 74 of 178,604 patients were diagnosed with leukemia and 135 of 176,587 patients were diagnosed with brain tumors. Positive associations were found between radiation dose from CT scans and leukemia (excess relative risks of leukemia per milligray (ERR/mGy) = 0.036) and brain tumors (ERR/mGy = 0.023). Compared with patients who received less than 5 mGy, the relative risk (RR) of leukemia for patients who received a cumulative dose of at least 30 mGy (mean dose = 51.13 mGy) was 3.18 and the RR of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose = 60.42 mGy) was 2.82. Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukemia, and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative absolute risks are small; nevertheless, radiation doses from CT scans ought to be kept as low as possible and alternative procedures that do not involve ionizing radiation should be considered if appropriate. (Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: A retrospective cohort study. Lancet 2012;380:499–505)

Leukemia Among Chernobyl Cleanup Workers

Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear. In a nested case-control study of leukemia among a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chernobyl nuclear power plant accident, excess relative risks per gray (ERR/Gy) of radiation doses were calculated. A significant linear dose response was found for all leukemia (n = 117; ERR/Gy = 2.38), CLL (ERR/Gy = 2.58), and non-CLL (ERR/Gy = 2.21). Altogether, 16% of leukemia cases (CLL = 18%; non-CLL = 15%) were attributed to radiation exposure. (Zablotska L, Bazyka D, Lubin JH, et al. Radiation and the risk of chronic lymphocytic and other leukemias among Chornobyl cleanup workers. Environ Health Perspect 2013;121:59–65)  

Radiation and Bone Sarcoma

Radiotherapy is associated with an increased incidence of second primary cancers, including osteosarcomas, especially after exposure in childhood. Using data from Surveillance, Epidemiology, and End Results (SEER) registries, this study evaluated whether radiation is related to other histologic types of bone sarcomas that are more common in adulthood, such as chondrosarcomas. A total of 159 second bone sarcomas were reported among 1,284,537 adult five-year cancer survivors. Compared with the general population, the risk of developing any bone sarcoma was increased by 25% among patients with no history of radiotherapy and by 257% among patients with a history of radiotherapy. The relative risk (RR) for radiotherapy for osteosarcoma was 5.08 and for chondrosarcoma was 1.54, with even greater risks for second sarcomas that arose in the radiotherapy field used to treat the first cancer (osteosarcoma: RR = 10.35; chondrosarcoma: RR = 8.21). These findings provide the first evidence of a likely association between radiation exposure and chondrosarcoma. (Wu LC, Kleinerman RA, Curtis RE, et al. Patterns of bone sarcomas as a second malignancy in relation to radiotherapy in adulthood and histologic type. Cancer Epidemiol Biomarkers Prev 2012;21:1993–1999)

Radiation Treatment-related Esophageal Cancer

The authors evaluated esophageal cancer risk after breast cancer in relation to radiation treatment dose and systemic therapy among 289,748 females from five population-based cancer registries who were survivors of breast cancer for 5 or more years. The authors abstracted radiation dosimetry and other information from medical records for 252 esophageal cases and 488 controls. The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location, with doses of 35 or more Gy associated with an odds ratio (OR) of 8.3. Patients who had received hormonal therapy for 5 years or less before esophageal cancer diagnosis had lower risk (OR = 0.4). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. The data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g., smoking). Esophageal cancer is a radiation dose–related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up. (Morton LM, Gilbert ES, Hall P, et al. Risk of treatment-related esophageal cancer among breast cancer survivors. Ann Oncol 2012;23:3081–3091)

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Renal Cancer

Risk from Smoking Modified by Hypertension and Obesity

The authors examined the association between smoking and renal cell carcinoma (RCC) among 1,217 cases and 1,235 population controls in the Kidney Cancer Study in Detroit, Michigan, and Chicago, Illinois. Among whites, increasing duration and number of pack-years of smoking were associated with increased risk of RCCs after adjusting for age, gender, education, study site, body mass index (BMI), and history of hypertension. Among blacks, RCC risk increased with duration of smoking but not other measures. Compared with current smokers, RCC risk decreased with increasing years of smoking cessation among both whites and blacks. The authors observed associations between smoking and RCC risk only among individuals who reported never having been diagnosed with hypertension (see Figure 5). Similarly, smoking was associated with increased risk of RCCs among non-obese individuals but not among those with BMI ≥ 30 kg/m2. The observation that smoking is associated with RCC only among non-obese individuals and those with no history of hypertension are novel findings. (Cote ML, Colt JS, Schwartz KL, et al. Cigarette smoking and renal cell carcinoma risk among black and white Americans: Effect modification by hypertension and obesity. Cancer Epidemiol Biomarkers Prev 2012;21:770–779)

Association of renal cell carcinoma with smoking, hypertension, and race

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Thyroid Cancer

I-131 Dose and Gene Expression

The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. The authors evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from persons exposed in the Chernobyl accident. The study was based on 63 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates with paired RNA specimens from fresh frozen tumor and normal tissue provided by the Chernobyl Tissue Bank. The authors confirmed that 11 of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) had a significant differential dose-expression relationship. This study is the first to provide direct human data on long-term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis. (Abend M, Pfeiffer RM, Ruf C, et al. Iodine-131 dose dependent gene expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident. PLoS One 2012;7:e39103)

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Back to the March 2013 issue of Linkage