Heather Spencer Feigelson

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 × 10−13; heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13–1.41; homozygote OR: 1.58, 95% c.i.: 1.40–1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 × 10−11; rs6983267 P = 6.62 × 10−10). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

Multiple loci identified in a genome-wide association study of prostate cancer

We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin—nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study—by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10−10). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 × 10−13 and P < 2.14 × 10−6). Loci on chromosome 10 include MSMB, which encodes β-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 × 10−5), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.

The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk

IMPORTANCE Increased use of computed tomography (CT) in pediatrics raises concerns about cancer risk from exposure to ionizing radiation. OBJECTIVES To quantify trends in the use of CT in pediatrics and the associated radiation exposure and cancer risk. DESIGN Retrospective observational study. SETTING Seven US health care systems. PARTICIPANTS The use of CT was evaluated for children younger than 15 years of age from 1996 to 2010, including 4 857 736 child-years of observation. Radiation doses were calculated for 744 CT scans performed between 2001 and 2011. MAIN OUTCOMES AND MEASURES Rates of CT use, organ and effective doses, and projected lifetime attributable risks of cancer. RESULTS The use of CT doubled for children younger than 5 years of age and tripled for children 5 to 14 years of age between 1996 and 2005, remained stable between 2006 and 2007, and then began to decline. Effective doses varied from 0.03 to 69.2 mSv per scan. An effective dose of 20 mSv or higher was delivered by 14% to 25% of abdomen/pelvis scans, 6% to 14% of spine scans, and 3% to 8% of chest scans. Projected lifetime attributable risks of solid cancer were higher for younger patients and girls than for older patients and boys, and they were also higher for patients who underwent CT scans of the abdomen/pelvis or spine than for patients who underwent other types of CT scans. For girls, a radiation-induced solid cancer is projected to result from every 300 to 390 abdomen/pelvis scans, 330 to 480 chest scans, and 270 to 800 spine scans, depending on age. The risk of leukemia was highest from head scans for children younger than 5 years of age at a rate of 1.9 cases per 10 000 CT scans. Nationally, 4 million pediatric CT scans of the head, abdomen/pelvis, chest, or spine performed each year are projected to cause 4870 future cancers. Reducing the highest 25% of doses to the median might prevent 43% of these cancers. CONCLUSIONS AND RELEVANCE The increased use of CT in pediatrics, combined with the wide variability in radiation doses, has resulted in many children receiving a high-dose examination. Dose-reduction strategies targeted to the highest quartile of doses could dramatically reduce the number of radiation-induced cancers.

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10−10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor–positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10−7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

Use of diagnostic imaging studies and associated radiation exposure for patients enrolled in large integrated health care systems, 1996-2010

CONTEXT Use of diagnostic imaging has increased significantly within fee-for-service models of care. Little is known about patterns of imaging among members of integrated health care systems. OBJECTIVE To estimate trends in imaging utilization and associated radiation exposure among members of integrated health care systems. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of electronic records of members of 6 large integrated health systems from different regions of the United States. Review of medical records allowed direct estimation of radiation exposure from selected tests. Between 1 million and 2 million member-patients were included each year from 1996 to 2010. MAIN OUTCOME MEASURE Advanced diagnostic imaging rates and cumulative annual radiation exposure from medical imaging. RESULTS During the 15-year study period, enrollees underwent a total of 30.9 million imaging examinations (25.8 million person-years), reflecting 1.18 tests (95% CI, 1.17-1.19) per person per year, of which 35% were for advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MRI], nuclear medicine, and ultrasound). Use of advanced diagnostic imaging increased from 1996 to 2010; CT examinations increased from 52 per 1000 enrollees in 1996 to 149 per 1000 in 2010, 7.8% annual increase (95% CI, 5.8%-9.8%); MRI use increased from 17 to 65 per 1000 enrollees, 10% annual growth (95% CI, 3.3%-16.5%); and ultrasound rates increased from 134 to 230 per 1000 enrollees, 3.9% annual growth (95% CI, 3.0%-4.9%). Although nuclear medicine use decreased from 32 to 21 per 1000 enrollees, 3% annual decline (95% CI, 7.7% decline to 1.3% increase), PET imaging rates increased after 2004 from 0.24 to 3.6 per 1000 enrollees, 57% annual growth. Although imaging use increased within all health systems, the adoption of different modalities for anatomic area assessment varied. Increased use of CT between 1996 and 2010 resulted in increased radiation exposure for enrollees, with a doubling in the mean per capita effective dose (1.2 mSv vs 2.3 mSv) and the proportion of enrollees who received high (>20-50 mSv) exposure (1.2% vs 2.5%) and very high (>50 mSv) annual radiation exposure (0.6% vs 1.4%). By 2010, 6.8% of enrollees who underwent imaging received high annual radiation exposure (>20-50 mSv) and 3.9% received very high annual exposure (>50 mSv). CONCLUSION Within integrated health care systems, there was a large increase in the rate of advanced diagnostic imaging and associated radiation exposure between 1996 and 2010.

Leisure Time Spent Sitting in Relation to Total Mortality in a Prospective Cohort of US Adults

The obesity epidemic is attributed in part to reduced physical activity. Evidence supports that reducing time spent sitting, regardless of activity, may improve the metabolic consequences of obesity. Analyses were conducted in a large prospective study of US adults enrolled by the American Cancer Society to examine leisure time spent sitting and physical activity in relation to mortality. Time spent sitting and physical activity were queried by questionnaire on 53,440 men and 69,776 women who were disease free at enrollment. The authors identified 11,307 deaths in men and 7,923 deaths in women during the 14-year follow-up. After adjustment for smoking, body mass index, and other factors, time spent sitting (> or = 6 vs. <3 hours/day) was associated with mortality in both women (relative risk = 1.34, 95% confidence interval (CI): 1.25, 1.44) and men (relative risk = 1.17, 95% CI: 1.11, 1.24). Relative risks for sitting (> or = 6 hours/day) and physical activity (<24.5 metabolic equivalent (MET)-hours/week) combined were 1.94 (95% CI: 1.70, 2.20) for women and 1.48 (95% CI: 1.33, 1.65) for men, compared with those with the least time sitting and most activity. Associations were strongest for cardiovascular disease mortality. The time spent sitting was independently associated with total mortality, regardless of physical activity level. Public health messages should include both being physically active and reducing time spent sitting.

Performance of common genetic variants in breast-cancer risk models.

BACKGROUND Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown. METHODS We used information on traditional risk factors and 10 common genetic variants associated with breast cancer in 5590 case subjects and 5998 control subjects, 50 to 79 years of age, from four U.S. cohort studies and one case-control study from Poland to fit models of the absolute risk of breast cancer. With the use of receiver-operating-characteristic curve analysis, we calculated the area under the curve (AUC) as a measure of discrimination. By definition, random classification of case and control subjects provides an AUC of 50%; perfect classification provides an AUC of 100%. We calculated the fraction of case subjects in quintiles of estimated absolute risk after the addition of genetic variants to the traditional risk model. RESULTS The AUC for a risk model with age, study and entry year, and four traditional risk factors was 58.0%; with the addition of 10 genetic variants, the AUC was 61.8%. About half the case subjects (47.2%) were in the same quintile of risk as in a model without genetic variants; 32.5% were in a higher quintile, and 20.4% were in a lower quintile. CONCLUSIONS The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information.

The American Cancer Society Cancer Prevention Study II Nutrition Cohort: Rationale, Study design, and baseline characteristics

Large‐scale, prospective cohort studies have played a critical role in discovering factors that contribute to variability in cancer risk in human populations. Epidemiologists and volunteers at the American Cancer Society (ACS) were among the first to establish such cohorts, beginning in the early 1950s and continuing through the present, and these ACS cohorts have made landmark contributions in many areas of epidemiologic research.

The American Cancer Society Cancer Prevention Study II Nutrition Cohort

Large‐scale, prospective cohort studies have played a critical role in discovering factors that contribute to variability in cancer risk in human populations. Epidemiologists and volunteers at the American Cancer Society (ACS) were among the first to establish such cohorts, beginning in the early 1950s and continuing through the present, and these ACS cohorts have made landmark contributions in many areas of epidemiologic research.