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Discovering the causes of cancer and the means of prevention

Scientific Highlights

March 2012 - Linkage Newsletter

Topics

All Cancers

Cancer Studies Among the Elderly

An approach is described for conducting population-based, case-control studies among the elderly by using linked SEER-Medicare data. Cases and controls are drawn from the population of Medicare beneficiaries older than age 65 years who reside in areas with cancer registries that participate in the SEER program. The strength of this type of study is the large size of the population, which allows study of less common cancers. The investigators discuss the cancer risk factors that can be assessed using Medicare claims, the methodology for timing of diagnoses and selecting controls, and the limitations of the approach. (Engels EA, Pfeiffer RM, Ricker W, et al. Use of Surveillance, Epidemiology, and End Results-Medicare data to conduct case-control studies of cancer among the U.S. elderly. Am J Epidemiol 2011;174:860–870)

Myotonic Muscular Dystrophy and Cancer Risk

The authors identified 1,658 patients with a myotonic muscular dystrophy (MMD) discharge diagnosis in the Swedish Hospital Discharge Register and Danish National Patient Registry between 1977 and 2008 and linked the patient data to cancer registries. A total of 104 patients developed cancer during follow-up, which corresponds to an observed rate of 73.4 per 10,000 person-years in MMD patients vs. an expected rate of 36.9 in the general Swedish and Danish populations combined (SIR = 2.0). Significant excess risks were observed for cancers of the endometrium (SIR = 7.6), brain (SIR = 5.3), ovary (SIR = 5.2), and colon (SIR = 2.9). Cancer risks were similar among women and men after excluding genital organ tumors. The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts. (Gadalla SM, Lund M, Pfeiffer RM, et al. Cancer risk among patients with myotonic muscular dystrophy. JAMA 2011;306:2480–2486)

Solid Organ Transplantation and Cancer Risk

Investigators studied overall patterns of cancer among 175,732 solid organ transplant recipients (kidney: 58.4%, liver: 21.6%, heart: 10.0%, lung: 4.0%) from the U.S. Scientific Registry of Transplant Recipients (1987–2008) with linked data from 13 state and regional cancer registries. During follow-up, transplant recipients were linked to 10,656 malignancy diagnoses, yielding an incidence of 1,375 per 100,000 person-years (SIR = 2.10; excess absolute risk = 719.3 per 100,000 person-years). Compared with the general population, recipients of a kidney, liver, heart, or lung transplant had an increased risk for various infection-related and -unrelated cancers. (Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among U.S. solid organ transplant recipients. JAMA 2011;306:1891–1901)

Women Exposed In Utero to Diethylstilbestrol

See article in this issue of Linkage. (Hoover RN, Hyer M, Pfeiffer RM, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. New Engl J Med 2011;365:1304–1314)

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Bladder Cancer

New Susceptibility Locus on Chromosome 18q12.3

GWAS and candidate gene–association studies of bladder cancer have identified 10 susceptibility loci. The authors conducted a meta-analysis of two published genome-wide scans and followed up the most significant association signals (17 SNPs in 10 genomic regions) in 1,382 cases and 2,201 controls from four studies. A combined analysis identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 and two highly correlated SNPs, rs10775480 and rs10853535. The signal localizes to SLC14A1, the gene for a urea transporter that regulates cellular osmotic pressure. The findings suggest that genetic variation in SLC14A1 may provide new insights into bladder carcinogenesis. (García-Closas M, Ye Y, Rothman N, et al. A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3. Hum Mol Genet 2011;20:4282–4289)

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Breast Cancer

Gene Variants by Breast Cancer Subtype

A recent multistage GWAS found that SNPs at 1p11.2 and 14q24.1 (RAD51L1) were associated with overall risk of breast cancer. To determine risks by tumor subtype, investigators analyzed data from case-control and cohort studies of the Breast Cancer Association Consortium, including 46,036 invasive breast cancer cases and 46,930 unaffected controls. These were evaluated by estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2, grade, node status, tumor size, and ductal or lobular morphology. The SNP at 1p11.2 showed significantly stronger associations with ER+ tumors (per-allele OR for ER+ tumors = 1.13). The association with ER+ tumors was more pronounced for tumors of lower grade and lobular histology. The SNPs at 14q24.1 were associated with risk for most tumor subtypes, including triple-negative breast cancers. (Figueroa JD, García-Closas M, Humphreys M, et al. Associations of common variants at 1p11.2 and 14q24.1 [RAD51L1] with breast cancer risk and heterogeneity by tumor subtype: Findings from the Breast Cancer Association Consortium. Hum Mol Genet 2011;20:4693–4706)

Physical Activity

In a prospective cohort of 73,049 Chinese women aged 40 to 70 years, the authors studied risk of breast cancer (717 incident cases) in relation to self-reported and work history–related physical activity, including adolescent and adult exercise, household activity, and walking and cycling for transportation. Risk was lower for women in the lowest quartile of average occupational sitting time and in the highest quartile of average occupational energy expenditure (adjusted HR = 0.81 and 0.73, respectively). Adult exercise at or above the recommended level (eight metabolic equivalent hours per week per year) was associated with lower risk (adjusted HR = 0.73) in postmenopausal women. Having both an active job and exercise participation did not confer an additional benefit, but other common daily activities were not associated with lower risk. (Pronk A, Ji BT, Shu XO, et al. Physical activity and breast cancer risk in Chinese women. Br J Cancer 2011;105:1443–1450)

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Cervical Cancer

HPV Screen-and-Treat Strategies

The authors conducted a population-based study in rural Nigeria to identify HPV prevalence and associated cervical abnormalities. Women aged 15 years and older were enrolled, and non-virgins had a cervical exam, including liquid-based cytology and polymerase chain reaction HPV DNA testing. Two-thirds of the invited women participated, and 14.7% had detectable carcinogenic HPV, a proportion that did not decline with age and showed slight peaks in the 15–29 and 60–69 age groups. Among women of the age typically considered for screen-and-treat programs (aged 30–49 years), 12.8% were HPV positive, and the positive predictive value (PPV) for high-grade or worse cytology was 16.4%. Comparatively, women younger than 30 years of age were more likely to be HPV positive (18.9%) with a lower PPV (4.2%). Among women aged 50 years and older (typically excluded from screening in resource-poor settings because inexpensive treatment is not available), HPV positivity was 14.2% with a PPV of 13.9%. In settings where HPV does not decline with age, HPV-based screen-and-treat programs may be feasible for mid-adult women because prevalence is sufficiently low and positivity predicts elevated risk of more easily treated pre-cancer. (Gage JC, Ajenifuja KO, Wentzensen NA, et al. The age-specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: Implications for screen-and-treat strategies. Int J Cancer 2011; May 31 [E-pub ahead of print])

Type-specific HPV Infection

The authors followed a large-scale, community-based cohort in Taiwan for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer, including invasive and in situ carcinoma. A total of 11,923 participants consented to HPV testing and cytology at baseline, and women who developed cervical cancer were identified from cancer and death registries. Of 10,123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV 16, HPV 58 (without HPV 16), or other carcinogenic HPV types (without HPV 16 or HPV 58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV negative at both visits (HR = 75.4). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age; the risks were 5.5%, 14.4%, and 18.1% for women aged 30–44 years, 45–54 years, and ≥ 55 years, respectively. Newly acquired infections were associated with a low risk of cervical cancer regardless of age. (Chen HC, Schiffman M, Lin CY, et al. Persistence of type-specific human papillomavirus infection and increased long-term risk of cervical cancer. J Natl Cancer Inst 2011;103:1387–1396)

Colorectal Cancer

Folate Intake

The authors examined the association between folate intake and colorectal cancer risk in the NIH-AARP Diet and Health Study, including 8.5 years of postfortification follow-up. During follow-up, 7,212 incident colorectal cancer cases were identified. A higher total folate intake was associated with a decreased risk (HR for ≥ 900 compared with < 200 μg/d = 0.70). The highest intakes specifically from supplements (HR = 0.82) or diet (HR = 0.81) were protective (see Figure 1). The pattern of associations was similar for the pre-fortification period, and no significant differences between time periods were observed. (Gibson TM, Weinstein SJ, Pfeiffer RM, et al. Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States.
Am J Clin Nutr 2011;94:1053–1062)

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Liver Cancer

Association of IL28B Genotype with Spontaneous Hepatitis C Virus Clearance

Investigators evaluated alternative genetic models for the association between variation in IL28B genotype (SNPs rs12979860 and rs8099917) and hepatitis C virus (HCV) clearance among 1,369 participants in the Urban Health Study, a multi-ethnic cohort of injection drug users. Chronic HCV infection puts infected individuals at risk for cirrhosis and hepatocellular carcinoma. After examining five potential genetic models (general, dominant, recessive, additive, and supra-additive [quadratic]), the investigators found that a quadratic genetic model based on rs12979860 described the association best. If confirmed, these findings may inform IL28B genotype–based clinical prediction models for treatment of chronic hepatitis C and the search for IL28B variants. (Shebl FM, Pfeiffer RM, Buckett D, et al. IL28B rs12979860 genotype and spontaneous clearance of hepatitis C virus in a multi-ethnic cohort of injection drug users: Evidence for a supra-additive association. J Infect Dis 2011;204:1843–1847)

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Lung Cancer

Early Gene Expression Signature

The authors measured genome-wide mRNA gene expression from lung tumor and unaffected lung tissue and from peripheral whole blood (PWB) from 73 adenocarcinoma cases and 80 controls in an effort to identify dysregulated genes associated with lung cancer that could be tested in blood to improve identification of at-risk patients. The authors discovered 50 dysregulated genes in stage I adenocarcinoma vs. control PWB samples. Eight of these genes (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor vs. uninvolved lung tissue samples in stage I cases, suggesting a similar pattern of cancer-related changes in PWB and lung tissue. Results were confirmed in two independent gene expression analyses in a blood-based, case-control study (n = 212) and a tumor–non-tumor paired tissue study (n = 54). The eight genes discriminated between patients with lung cancer and healthy controls with high accuracy. (Rotunno M, Hu N, Su H, et al. A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma. Cancer Prev Res [Phila] 2011;4:1599–1608)

Variation at Chromosome 12p13.33

Although lung cancer is largely caused by tobacco smoking, inherited susceptibility plays an etiologic role. Previous GWAS in European populations have robustly demonstrated three polymorphic variations influencing lung cancer risk. In a GWAS of 5,355 European cases of smoking-related lung cancer and 4,344 smoking controls, the authors conducted a pathway-based analysis based on histologic subtypes of lung cancer, with 19,082 SNPs mapping to 917 genes in the inflammation pathway. A susceptibility locus for squamous cell lung carcinoma (SQ) was identified at 12p13.33 (RAD52, rs6489769), and the association was replicated in three independent samples, totaling 3,359 SQ cases and 9,100 controls (OR = 1.20). The combination of pathway-based approaches and information on disease-specific subtypes should improve the identification of susceptibility loci in heterogeneous diseases. (Shi J, Chatterjee N, Rotunno M, et al. Inherited variation at chromosome 12p13.33 including RAD52 influences squamous cell lung carcinoma risk. Cancer Discov 2011; December 7 [E-pub ahead of print])

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Melanoma

Genetic Susceptibility

See article in this issue of Linkage. (Yokoyama S, Woods SL, Boyle GM, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011;480:99–103)

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Nutrition

GWAS of Circulating Vitamin E and Retinol Levels

A series of GWAS were conducted to investigate common genetic variants associated with circulating levels of nutrients. The results for vitamin E and retinol are presented here based on data from two studies, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. 

Vitamin E: Three genomic loci were found to be associated with vitamin E (alpha-tocopherol) levels. Two were novel SNPs, rs2108622 on 19pter-p13.11 and rs11057830 on 12q24.3, and the authors confirmed a previously reported locus marked by rs964184 on 11q23.3. The three SNPs have been reported to be associated with lipid metabolism and/or regulation. The authors replicated these findings in a combined meta-analysis with two independent samples. (Major JM, Yu K, Wheeler W, et al. Genome-wide association study identifies common variants associated with circulating vitamin E levels. Hum Mol Genet 2011;20:3876–3883)

Retinol: Circulating levels of retinol were associated with two independent SNPs, rs1667255 (p = 2.30 x 10–17) and rs10882272 (p = 6.04 x 10–12), located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes, which encode major carrier proteins of retinol. The association was then replicated with rs10882272 in RBP4 in samples from the Nurses’ Health Study and the Invecchiare in Chianti Study, thus suggesting evidence for gender dimorphism (p for interaction = 1.31 x 10–5). (Mondul AM, Yu K, Wheeler W, et al. Genome-wide association study of circulating retinol levels. Hum Mol Genet 2011;20:4724–4731)

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Oropharyngeal Cancer

Rising Incidence Associated with HPV Infection

Investigators determined HPV status for all 271 oropharyngeal cancers (1984–2004) collected by the three population-based cancer registries in the SEER Residual Tissue Repositories Program and compared survival of HPV-positive and HPV-negative patients (see Figure 2). Analyses confirmed that increases in the population-level incidence of oropharyngeal cancers in the United States are caused by HPV infection. (Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:4294–4301)

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Pancreatic Cancer

Mitochondrial DNA Copy Number

To test whether higher mitochondrial DNA (mtDNA) copy number is associated with an increase in incident pancreatic cancer, the authors conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers aged 50 to 69 years at baseline. During 12 years of follow-up, 203 incident cases of pancreatic adenocarcinoma occurred among participants, and whole blood samples were used for mtDNA extraction. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64) and in continuous models (OR = 1.14), particularly for cases diagnosed during the first seven years of follow-up (OR = 2.14, continuous OR = 1.21), but not for cases occurring after seven years (OR = 1.14, continuous OR = 1.05). The results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and may serve as a biomarker of risk. (Lynch SM, Weinstein SJ, Virtamo J, et al. Mitochondrial DNA copy number and pancreatic cancer in the Alpha-Tocopherol Beta-Carotene cancer prevention study. Cancer Prev Res [Phila] 2011;4:1912–1919)

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Prostate Cancer

Gene Variants and Pesticide Exposure

As part of exploring the role of oxidative DNA damage in the pesticide-associated risk of prostate cancer, the authors studied the interactions between pesticide exposures and genetic variation in base excision repair (BER) pathway genes, the predominant pathway involved in repairing oxidative damage. The authors evaluated interactions between 39 pesticides and 394 tag SNPs for 31 BER pathway genes among 776 prostate cancer patients and 1,444 male controls in a nested, case-control study of pesticide applicators in the Agricultural Health Study. Notable interactions were found between several pesticides and BER gene variants with respect to prostate cancer, but only fonofos x NEIL3 rs1983132 showed an interaction fitting an expected biological pattern that remained significant after adjustment for multiple comparisons. Results were consistent with a mechanism of effect involving oxidative stress. (Barry KH, Koutros S, Berndt SI, et al. Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk. Environ Health Perspect 2011;119:1726–1732)

New Susceptibility Loci

To identify loci that influence susceptibility to prostate cancer, the authors conducted a GWAS among 2,782 advanced prostate cancer cases and 4,458 controls with 571,243 SNPs. Based on in silico replication of 4,679 SNPs in two published GWAS with 7,358 prostate cancer cases and 6,732 controls, the authors identified a new susceptibility locus associated with overall prostate cancer risk at 2q37.3 (rs2292884). They also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774). The estimated per-allele ORs for these loci (OR = 1.14 for rs2292884 and OR = 1.17 for rs902774) did not differ between advanced and non-advanced prostate cancer. (Schumacher FR, Berndt SI, Siddiq A, et al. Genome-wide association study identifies new prostate cancer susceptibility loci. Hum Mol Genet 2011;20:3867–3875)

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Renal Cell Carcinoma

Fine Mapping Chromosome 2p21

In a follow-up to a recent GWAS that identified a locus in chromosome 2p21 associated with the risk of RCC, a fine mapping analysis was conducted in a region that includes EPAS1. The authors genotyped 59 tagged common SNPs in 2,278 cases of RCC and 3,719 controls of European background and observed a novel signal for rs9679290 (p = 5.75 x 10–8, per-allele OR = 1.27). Imputation of common SNPs surrounding rs9679290 yielded two additional signals, rs4953346 (p = 4.09 x 10–14) and rs12617313 (p = 7.48 x 10–12), both highly correlated with rs9679290 but, interestingly, not correlated with the two SNPs reported in the GWAS, rs11894252 and rs7579899. Genotype analysis of rs12617313 confirmed an association with RCC risk (p = 1.72 x 10–9, per-allele OR = 1.28). The authors concluded that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants. (Han SS, Yeager M, Moore LE, et al. The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma. Hum Mol Genet 2011; November 23 [E-pub ahead of print])

Hypertension and Racial Disparities

The authors examined the association between hypertension and risk of RCC in a population-based, case-control study involving 843 whites and 358 blacks with RCC, along with controls that included 707 whites and 519 blacks. After adjustment for demographic characteristics, smoking, body mass index, and family history of cancer, hypertension doubled renal cancer risk overall (OR = 2.0, whites: OR = 1.9, blacks: OR = 2.8). ORs increased with time after hypertension diagnosis, reaching 4.1 for blacks and 2.6 for whites after 25 years (see Figure 3). The findings indicate that hypertension is a risk factor for RCC among both blacks and whites; these results may explain a substantial portion of the higher incidence of RCC among the black population. (Colt JS, Schwartz K, Graubard BI, et al. Hypertension and risk of renal cell carcinoma among white and black Americans. Epidemiology 2011;22:797–804)

VHL Gene Inactivation

The authors examined the role of the von Hippel-Lindau gene (VHL) and epigenetic inactivation among 507 sporadic RCC, including 470 clear cell renal tumors (ccRCC). Case-only multivariate analyses were conducted to identify associations between genetic alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed in 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue. Risk of having genetic VHL inactivation was inversely associated among former smokers (OR = 0.70) and current smokers (OR = 0.56). Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting an inherited propensity to epigenetic variation in renal tissue. Tumors from current smokers lacking VHL alterations may represent an entity distinct from inactivated cases. (Moore LE, Nickerson ML, Brennan P, et al. Von Hippel-Lindau [VHL] inactivation in sporadic clear cell renal cancer: Associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet 2011;7:e1002312)

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