Large body size has been associated with a reduced risk of premenopausal breast cancer in non-Hispanic white women. Data on other racial/ethnic populations are limited. The authors examined the association between premenopausal breast cancer risk and adult body size in 672 cases and 808 controls aged ≥35 years from a population-based case-control study conducted in 1995–2004 in the San Francisco Bay Area (Hispanics: 375 cases, 483 controls; African Americans: 154 cases, 160 controls; non-Hispanic whites: 143 cases, 165 controls). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Height was associated with increased breast cancer risk (highest vs. lowest quartile: odds ratio = 1.77, 95% confidence interval: 1.23, 2.53; Ptrend < 0.01); the association did not vary by hormone receptor status or race/ethnicity. Body mass index (measured as weight (kg) divided by height (m) squared) was inversely associated with risk in all 3 racial/ethnic groups, but only for estrogen receptor– and progesterone receptor–positive tumors (body mass index ≥30 vs. <25: odds ratio = 0.42; 95% confidence interval: 0.29, 0.61). Other body size measures (current weight, body build, adult weight gain, young adult weight and body mass index, waist circumference, and waist-to-height ratio) were similarly inversely associated with risk of estrogen receptor– and progesterone receptor–positive breast cancer but not estrogen receptor– and progesterone receptor–negative disease. Despite racial/ethnic differences in body size, inverse associations were similar across the 3 racial/ethnic groups when stratified by hormone receptor status.

Background

The role of moderate physical activity and life patterns of activity in reducing endometrial cancer risk remains uncertain.

Methods

We assessed lifetime histories of activity from recreation, transportation, chores, and occupation and other risk factors in a population-based case-control study of endometrial cancer conducted in the San Francisco Bay area. The analysis was based on 472 newly diagnosed cases ascertained by the regional cancer registry and 443 controls identified by random-digit dialing who completed an in-person interview.

Results

Reduced risks associated with greater lifetime physical activity (highest vs. lowest tertile) were found for both total activity (odds ratio (OR) = 0.61 (95% confidence interval (CI) = 0.43–0.87, ptrend = 0.01) and activity of moderate intensity (OR=0.44, 95% CI=0.30–0.64, ptrend < 0.0001). Compared to women with low lifetime physical activity (below median), those with greater activity throughout life had the highest reduction in risk (OR=0.62, 95% CI=0.44–0.88). Inverse associations were stronger in obese and overweight women, but differences were not statistically significantly different from those in normal weight women.

Conclusion

These findings suggest that physical activity in adulthood, even of moderate intensity, may be effective in lowering the risk of endometrial cancer, particularly among those at highest risk for this disease.

Impact

The results emphasize the importance of evaluating lifetime histories of physical activity from multiple sources, including both recreational and non-recreational activities of various intensities, in order to fully understand the relation between physical activity and disease risk.

Background

Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight.

Methods

We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2651 breast cancer cases and 2520 controls of African or European ancestry that were pooled from seven studies.

Results

We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk.

Conclusion

The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist.

Impact

The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk.

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

High dietary intake of calcium has been classified as a probable cause of prostate cancer although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX-2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet-gene interactions by conditional logistic regression. Compared to men in the lowest quartile of calcium intake, men in the highest quartile had an approximately two-fold increased risk of localized and advanced prostate cancer (odds ratio [OR]= 2.20, 95% confidence interval [CI]= 1.40, 3.46), with a significant dose-response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR= 0.41, 95% CI = 0.19, 0.90). The gene-calcium interaction was statistically significant (p=0.03). Among men with calcium intake below the median (680 mg/day), carriers of the G allele had an approximately 50% decreased risk compared to men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium.

The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case–control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ≥ 30 kg/m2) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m2) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

Consumption of red meat, particularly well done meat, has been associated with increased prostate cancer risk. High temperature cooking methods such as grilling and barbequeing may produce heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) which are known carcinogens. We assessed the association with meat consumption and estimated HCA and PAH exposure in a population-based case-control study of prostate cancer. Newly diagnosed cases aged 40–79 years (531 advanced cases, 195 localized cases) and 527 controls were asked about dietary intake, including usual meat cooking methods and doneness levels. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. For advanced prostate cancer, but not localized disease, increased risks were associated with higher consumption of hamburgers (OR=1.79. CI=1.10–2.92), processed meat (OR=1.57, CI=1.04, 2.36), grilled red meat (OR=1.63, CI=0.99–2.68), and well done red meat (OR=1.52, CI=0.93–2.46), and intermediate intake of 2-amino-1-methyl1-6-phenylimidazo[4,5-b]pyridine (PhIP) (quartile 2 vs. 1: OR=1.41, CI=0.98–2.01; quartile 3 vs. 1: OR=1.42, CI=0.98–2.04), but not for higher intake. White meat consumption was not associated with prostate cancer. These findings provide further evidence that consumption of processed meat and red meat cooked at high temperature is associated with increased risk of advanced, but not localized prostate cancer.

Purpose

Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).

Patients and Methods

Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.

Results

We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.

Conclusion

These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.

Background

Adult body size has long been known to influence breast cancer risk, and there is now increasing evidence that childhood and adolescent body size may also play a role.

Methods

We assessed the association with body size at ages 10, 15, and 20 years in 475 premenopausal and 775 postmenopausal Hispanic women who participated in a population-based case-control study of breast cancer conducted from 1995 to 2004 in the San Francisco Bay Area. We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with self-reported relative weight compared to peers and body build at ages 10, 15, and 20 years.

Results

In premenopausal women, we found inverse associations with relative weight compared to peers, with ORs of 0.63 (Ptrend = 0.05), 0.31 (Ptrend < 0.01), and 0.44 (Ptrend = 0.02) for heavier vs. lighter weight at ages 10, 15, and 20 years, respectively. These inverse associations were stronger in currently overweight women and US-born women and did not differ significantly for case groups defined by estrogen receptor status. Inverse associations were stronger in US-born than foreign-born Hispanics. In postmenopausal women not currently using hormone therapy, inverse associations with relative weight were limited to US-born Hispanics.

Conclusions

Large body size at a young age may have a long-lasting influence on breast cancer risk in premenopausal, and possibly postmenopausal, Hispanic women that is independent of current BMI.

Impact

These findings need to be weighed against adverse health effects associated with early-life obesity.

Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10−24 versus OR = 1.04, P = 6.1 × 10−5]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.

Purpose

Our study examines whether reproductive and hormonal factors prior to, at the time of, or subsequent to, radiation treatment for a first primary breast cancer, modify the risk of radiation-induced second primary breast cancer.

Methods and Materials

The Women’s Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1,399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.

Results

Women who were nulliparous at diagnosis and exposed to ≥1 gray (Gy) to the contralateral breast, had a greater risk of CBC than matched unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0). No increased risk was seen in RT-exposed parous women (RR=1.1, 95% CI 0.8–1.4). Women treated with RT who later became pregnant (n=8 cases and 9 controls) had a greater risk of CBC (RR=6.0, 95% CI 1.3, 28.4) than unexposed women (n=4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding or menopausal status at the time of first breast cancer diagnosis.

Conclusion

Nulliparous women treated with RT were at an increased risk of CBC. Although based on small numbers, women who become pregnant after first diagnosis also appear to be at an increased risk of radiation-induced CBC.

Background A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.

Methods Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.

Results Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.

Conclusions Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research.

Purpose

Breast cancer incidence is lower in African Americans than in Caucasian Americans. However, African-American women have higher breast cancer mortality rates and tend to be diagnosed with earlier-onset disease. Identifying factors correlated to the racial/ethnic variation in the epidemiology of breast cancer may provide better understanding of the more aggressive disease at diagnosis. Truncating germline mutations in PALB2 have been identified in approximately 1% of early-onset and/or familial breast cancer cases. To date, PALB2 mutation testing has not been performed in African-American breast cancer cases.

Methods

We screened for germline mutations in PALB2 in 139 African-American breast cases by denaturing high-performance liquid chromatography and direct sequencing.

Results

Twelve variants were identified in these cases and none caused truncation of the protein. Three missense variants, including two rare variants (P8L and T300I) and one common variant (P210L), were predicted to be pathogenic, and were located in a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding. We investigated and found no significant association between the P210L variant and breast cancer risk in a small case-control study of African-American women.

Conclusions

This study adds to the literature that PALB2 mutations, although rare, appear to play a role in breast cancer in all populations investigated to date.

Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls aged 6–17 years. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI) and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer.

Mitochondria play important roles in cellular energy production, free radical generation and apoptosis. In a previous report in Cancer Research, the mitochondrial DNA (mtDNA) G10398A (Thr → Ala) polymorphism was associated with breast cancer risk in African-American women. Here, we seek to replicate the association by genotyping the G10398A polymorphism in three established population-based case-control studies of breast cancer in African-American women. The 10398A allele was not significantly associated with risk in any of the studies [San Francisco study (542 cases, 282 controls, odds ratio (OR) = 1.73; 95% confidence interval (CI): 0.87, 3.47, P = 0.12); Multiethnic Cohort (391 cases, 460 controls, OR = 1.08; 95% CI: 0.62, 1.86, P = 0.79); CARE/LIFE study (524 cases, 236 controls, OR = 0.81; 95% CI: 0.43, 1.52, P = 0.50)]. When pooling the data across the three studies (1456 cases and 978 controls), no significant association was observed with the 10398A allele (OR = 1.14; 95% CI: 0.80, 1.62, P = 0.47, P heterogeneity=0.30). In analysis of advanced breast cancer cases (n=674), there also was no significant association (OR = 1.18; 95% CI: 0.76, 1.82, P = 0.46). Our results do not support the hypothesis that the mtDNA G10398A polymorphism is a marker of breast cancer risk in African Americans as previously reported.

Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n=4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the three years prior to diagnosis was associated with a 34% lower risk of death (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85) for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age ≥50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.

Background

Breast cancer incidence is higher in US-born Hispanic women than foreign-born Hispanics, but no studies have examined how these rates have changed over time. To better inform cancer control efforts, we examined incidence trends by nativity and incidence patterns by neighborhood socioeconomic status (SES) and Hispanic enclave (neighborhoods with high proportions of Hispanics or Hispanic immigrants).

Methods

Information regarding all Hispanic women diagnosed with invasive breast cancer between 1988 and 2004 were obtained from the California Cancer Registry. Nativity was imputed from Social Security number for the 27% of cases with missing birthplace information. Neighborhood variables were developed from Census data.

Results

From 1988 to 2004, incidence rates for US-born Hispanics were parallel, but lower than, those of non-Hispanic whites, showing an annual 6% decline from 2002 to 2004. Foreign-born Hispanics had an annual 4% increase in incidence rates from 1995 to 1998 and a 1.4% decline thereafter. Rates were 38% higher for US- than foreign-born Hispanics, with elevations more pronounced for localized than regional/distant disease, and for women > 50 years of age. Residence in higher SES and lower Hispanic enclave neighborhoods were independently associated with higher incidence, with Hispanic enclave having a stronger association than SES.

Conclusions

Compared to foreign-born, US-born Hispanic women in California had higher prevalence of breast cancer risk factors, suggesting that incidence patterns largely reflects these differences in risk factors.

Impact

Further research is needed to separate the effects of individual- and neighborhood-level factors that impact incidence in this large and growing population.

The incidence of breast cancer is 35% lower in Hispanic women living in the San Francisco Bay Area than in non-Hispanic white women. We have previously described a significant association between genetic ancestry and risk of breast cancer in a sample of US Hispanics/Latinas. We re-tested the association in women residing in Mexico because of the possibility that the original finding may be confounded by US specific unmeasured environmental exposures. We genotyped a set of 106 ancestry informative markers (AIMs) in 846 Mexican women with breast cancer and 1,035 unaffected controls and estimated genetic ancestry using a maximum likelihood method. Odds ratios (OR) and 95% confidence intervals (CI) for ancestry modeled as a categorical and continuous variable were estimated using logistic regression and adjusted for reproductive and other known risk factors. Greater European ancestry was associated with increased breast cancer risk in this new and independent sample of Mexican women residing in Mexico. Compared to women with 0-25% European ancestry, the risk was increased for women with 51-75% and 76-100% European ancestry (OR=1.35, 95% CI: 0.96-1.91 and 2.44, 95% CI: 0.94-6.35 respectively, p for trend=0.044). For every 25% increase in European ancestry (modeled as a continuous variable) there was a 20% increase in risk of breast cancer (95% CI: 1.03-1.41, p=0.019). These results suggest that non-genetic factors play a crucial role in explaining the difference in breast cancer incidence between Latinas and non-Latina white women and it also points out to the possibility of a genetic component to this difference.

African American women with breast cancer present more commonly with aggressive tumors that do not express the estrogen receptor (ER) and progesterone receptor (PR) compared with European American women. Whether this disparity is the result of inherited factors has not been established. We performed an admixture-based genome-wide scan to search for risk alleles for breast cancer that are highly differentiated in frequency between African American and European American women and may contribute to specific breast cancer phenotypes, such as ER negative (ER−) disease. African American women with invasive breast cancer (n=1,484) were pooled from 6 population-based studies and typed at ~1,500 ancestry informative markers (AIMs). We investigated global genetic ancestry and performed a whole genome admixture scan searching for breast cancer predisposing loci in association with disease phenotypes. We found a significant difference in ancestry between ER+PR+ and ER−PR− women, with higher European ancestry among ER+PR+ individuals, after controlling for possible confounders (OR for a 0 to 1 change in European ancestry proportion=2.84, 95% CI: 1.13–7.14, p=0.026). Women with localized tumors had higher European ancestry than women with non-localized tumors (OR=2.65, CI: 1.11–6.35, p=0.029). No genome-wide statistically significant associations were observed between European or African ancestry at any specific locus and breast cancer, or in analyses stratified by ER/PR status, stage or grade. In summary, in African American women genetic ancestry is associated with ER/PR status and disease stage. However, we found little evidence that genetic ancestry at any one region contributes significantly to breast cancer risk or hormone receptor status.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33).

We consider the feasibility of reusing existing control data obtained in genetic association studies in order to reduce costs for new studies. We discuss controlling for the population differences between cases and controls that are implicit in studies utilizing external control data. We give theoretical calculations of the statistical power of a test due to Bourgain et al (Am J Human Genet 2003), applied to the problem of dealing with case-control differences in genetic ancestry related to population isolation or population admixture. Theoretical results show that there may exist bounds for the non-centrality parameter for a test of association that places limits on study power even if sample sizes can grow arbitrarily large. We apply this method to data from a multi-center, geographically-diverse, genome-wide association study of breast cancer in African-American women. Our analysis of these data shows that admixture proportions differ by center with the average fraction of European admixture ranging from approximately 20% for participants from study sites in the Eastern United States to 25% for participants from West Coast sites. However, these differences in average admixture fraction between sites are largely counterbalanced by considerable diversity in individual admixture proportion within each study site. Our results suggest that statistical correction for admixture differences is feasible for future studies of African-Americans, utilizing the existing controls from the African-American Breast Cancer study, even if case ascertainment for the future studies is not balanced over the same centers or regions that supplied the controls for the current study.

Author Summary

This paper discusses and provides unique insight into an important problem raised by the current state of genetic studies into disease susceptibility, namely whether we can reuse genetic data from participants genotyped as controls in one study when cases (people with a disease of interest) are obtained from other studies, or whether each new study needs its own controls. We are interested in whether studies where cases and controls are sampled differently will give correct answers and are as powerful statistically as when new control data is also genotyped. Because of the huge investments made recently in large scale genotyping of cases and controls for various diseases, this is a timely question. This question is especially important in understanding the genetic causes of disease in as-yet relatively understudied population groups, such as African-Americans, in order to speed up progress when this is possible. We give theoretical results about the power of studies that reuse existing control genotypes based on statistical considerations. We also provide analysis of real data from a major study of the genetic causes of breast cancer in African-American women in order to shed practical light upon this issue.

Background

Contralateral second primary breast cancers occur in 4% of female breast cancer survivors. Little is known about differences in risk for second primary breast cancers related to the estrogen and progesterone receptor (hormone receptor [HR]) status of the first tumor.

Methods

We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for contralateral primary breast cancers among 4927 women diagnosed with a first breast cancer between January 1, 1992, and December 31, 2004, using the National Cancer Institute’s Surveillance, Epidemiology, and End Results database.

Results

For women whose first breast tumors were HR positive, risk of contralateral primary breast cancer was elevated, compared with the general population, adjusted for age, race, and calendar year (SIR = 2.22, 95% CI = 2.15 to 2.29, absolute risk [AR] = 13 cases per 10 000 person-years [PY]), and was not related to the HR status of the second tumor. For women whose first breast tumors were HR negative, the risk of a contralateral primary tumor was statistically significantly higher than that for women whose first tumors were HR positive (SIR = 3.57, 95% CI = 3.38 to 3.78, AR = 18 per 10 000 PY), and it was associated with a much greater likelihood of an HR-negative second tumor (SIR for HR-positive second tumors = 1.94, 95% CI = 1.77 to 2.13, AR = 20 per 10 000 PY; SIR for HR-negative second tumors = 9.81, 95% CI = 9.00 to 10.7, AR = 24 per 10 000 PY). Women who were initially diagnosed with HR-negative tumors when younger than 30 years had greatly elevated risk of HR-negative contralateral tumors, compared with the general population (SIR = 169, 95% CI = 106 to 256, AR = 77 per 10 000 PY). Incidence rates for any contralateral primary cancer following an HR-negative or HR-positive tumor were higher in non-Hispanic blacks, Hispanics, and Asians or Pacific Islanders than in non-Hispanic whites.

Conclusions

Risk for contralateral second primary breast cancers varies substantially by HR status of the first tumor, age, and race and/or ethnicity. Women with HR-negative first tumors have nearly a 10-fold elevated risk of developing HR-negative second tumors, compared with the general population. These findings warrant intensive surveillance for second breast cancers in women with HR-negative tumors.

Background

Documentation of language usage in medical settings could be effective in identifying and addressing language barriers and would improve understanding of health disparities.

Methods

This study evaluated the availability and accuracy of medical records information on language for 1,664 cancer patients likely to have poor English proficiency. Accuracy was assessed by comparison to language obtained from interview-based research studies.

Results

For patients diagnosed at facilities where information on language was not abstracted electronically, 81.6% had language information in their medical records, most often in admissions documents. For all 37 hospitals, agreement between medical records and interview language was 79.3% overall and was greater for those speaking English than another language.

Conclusions

Language information is widely available in hospital medical records of cancer patients. However, for the data to be useful for research and reducing language barriers in medical care, the information must be collected in a consistent and accurate manner.

In large scale genome-wide association studies based on high density single nucleotide polymorphism (SNP) genotyping array, the quantity and quality of available genomic DNA (gDNA) is a practical problem. We examined the feasibility of utilizing the Multiple Displacement Amplification (MDA) method of whole genome amplification (WGA) for such a platform. The Affymetrix Early Access Mendel Nsp 250K GeneChip was used for genotyping 224,940 SNPs/sample for 28 DNA samples. We compared the call concordance using 14 gDNA samples and their corresponding 14 WGA samples. The overall mean genotype call rates in gDNA and corresponding WGA samples were comparable [97.07% (95% CI 96.17–97.97) vs. 97.77% (95% CI 97.26–98.28), p=0.154]. Reproducibility of the platform, calculated as concordance in duplicate samples, was 99.45%. Overall genotypes for 97.74% (95% CI 97.03–98.44) of SNPs were concordant between gDNA and WGA samples. Restricting the analysis to well performing SNPs (successful genotyping in gDNA and WGA in >90% samples), on average, 99.11% (95% CI 98.80–99.42) of the SNPs were concordant and overall a SNP showed a discordant call in 0.92% (95% CI 0.90–0.94) of paired samples. In a pair of gDNA and WGA DNA, similar concordance was reproducible on Illumina’s Infinium platform as well. Although copy number analysis revealed a total of seven small telomeric regions in six chromosomes with loss of copy number, the estimated genome representation was 99.29%. In conclusion, our study confirms that high density oligonucleotide array-based genotyping can yield reproducible data and MDA-WGA DNA products can be effectively used for genome-wide SNP genotyping analysis.

Purpose

Patients with early-onset breast and/or ovarian cancer frequently wish to know if they inherited a mutation in one of the cancer susceptibility genes, BRCA1 or BRCA2. Accurate carrier prediction models are needed to target costly testing. Two widely used models, BRCAPRO and BOADICEA, were developed using data from non-Hispanic Whites (NHW), but their accuracies have not been evaluated in other racial/ethnic populations.

Methods

We evaluated the BRCAPRO and BOADICEA models in a population-based series of African-American, Hispanic and NHW breast cancer patients tested for BRCA1 and BRCA2 mutations. We assessed model calibration by evaluating observed versus predicted mutations and attribute diagrams, and model discrimination using areas under receiver operating characteristic curves (AUCs).

Results

Both models were well-calibrated within each racial/ethnic group, with some exceptions. BOADICEA over-predicted mutations in African Americans and older NHWs, and BRCAPRO under-predicted in Hispanics. In all racial/ethnic groups, the models over-predicted in cases whose personal and family histories indicated greater than 80% probability of carriage. The two models showed similar discrimination in each racial/ethnic group, discriminating least well in Hispanics. For example, BRCAPRO’s AUCs were 83% (95% confidence interval 63–93%) for NHWs, compared to 74% (59–85%) for African Americans and 58% (45–70%) for Hispanics.

Conclusions

The models’ poor performance for Hispanics may be due to model misspecification in this racial/ethnic group. However, it also may reflect racial/ethnic differences in the distributions of personal and family histories among breast cancer cases in the Northern California population.