Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a ...representative clinical sample.
Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.
In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.
Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.
Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and ...oxides of nitrogen were estimated by kriging (NOx, NO2, PM10, PM2.5), land use regression (LUR, NOx, NO2) and California Line Source Dispersion model (CALINE4, NOx, PM2.5) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993–1996) through 2010. Cox proportional hazards models were used to examine the associations between time‐varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion ppb) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 μg/m3) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio HR = 1.35, 95% confidence interval 95% CI: 1.02–1.79), NO2 (HR = 1.44, 95% CI: 1.04–1.99), PM10 (HR = 1.29, 95% CI: 1.07–1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15–2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01–1.45) and NO2 (HR = 1.26, 95% CI: 1.00–1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near‐roadway exposures, on the risk of breast cancer is warranted.
What's new?
Prior studies of air pollution and breast cancer generally have employed one method of exposure assessment and have focused on white women, with inconsistent results. Here, three exposure assessment methods, kriging interpolation, land use regression (LUR), and California Line Source Dispersion model (CALINE4), were used to investigate associations between long‐term air pollutant exposure and breast cancer risk in the Southern California Multiethnic Cohort. Breast cancer risk was increased in association with air pollution exposure among women residing near major roads according to kriging and LUR measures.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. ...Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report a genome-wide association study of cutaneous squamous cell carcinoma conducted among non-Hispanic white members of the Kaiser Permanente Northern California health care system. The study ...includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5,600 controls). Combined analysis of screening and replication phases identified 10 loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5 × 10−8. Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate squamous cell carcinoma risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated squamous cell carcinoma risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited squamous cell carcinoma susceptibility.
Clinicians use different breast cancer risk models for patients considered at average and above-average risk, based largely on their family histories and genetic factors. We used longitudinal cohort ...data from women whose breast cancer risks span the full spectrum to determine the genetic and nongenetic covariates that differentiate the performance of two commonly used models that include nongenetic factors - BCRAT, also called Gail model, generally used for patients with average risk and IBIS, also called Tyrer Cuzick model, generally used for patients with above-average risk.
We evaluated the performance of the BCRAT and IBIS models as currently applied in clinical settings for 10-year absolute risk of breast cancer, using prospective data from 1,857 women over a mean follow-up length of 8.1 years, of whom 83 developed cancer. This cohort spans the continuum of breast cancer risk, with some subjects at lower than average population risk. Therefore, the wide variation in individual risk makes it an interesting population to examine model performance across subgroups of women. For model calibration, we divided the cohort into quartiles of model-assigned risk and compared differences between assigned and observed risks using the Hosmer-Lemeshow (HL) chi-squared statistic. For model discrimination, we computed the area under the receiver operator curve (AUC) and the case risk percentiles (CRPs).
The 10-year risks assigned by BCRAT and IBIS differed (range of difference 0.001 to 79.5). The mean BCRAT- and IBIS-assigned risks of 3.18% and 5.49%, respectively, were lower than the cohort's 10-year cumulative probability of developing breast cancer (6.25%; 95% confidence interval (CI) = 5.0 to 7.8%). Agreement between assigned and observed risks was better for IBIS (HL X4(2) = 7.2, P value 0.13) than BCRAT (HL X4(2) = 22.0, P value <0.001). The IBIS model also showed better discrimination (AUC = 69.5%, CI = 63.8% to 75.2%) than did the BCRAT model (AUC = 63.2%, CI = 57.6% to 68.9%). In almost all covariate-specific subgroups, BCRAT mean risks were significantly lower than the observed risks, while IBIS risks showed generally good agreement with observed risks, even in the subgroups of women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative).
Models developed using extended family history and genetic data, such as the IBIS model, also perform well in women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Extending such models to include additional nongenetic information may improve performance in women across the breast cancer risk continuum.
A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer logarithm of odds (LOD) = ...7.1. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10⁻⁹) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.
Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene ...expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.
CONTEXT Information on the prevalence of pathogenic BRCA1 mutation carriers in racial/ethnic minority populations is limited. OBJECTIVE To estimate BRCA1 carrier prevalence in Hispanic, African ...American, and Asian American female breast cancer patients compared with non-Hispanic white patients with and without Ashkenazi Jewish ancestry. DESIGN, SETTING, AND PARTICIPANTS We estimated race/ethnicity-specific prevalence of BRCA1 in a population-based, multiethnic series of female breast cancer patients younger than 65 years at diagnosis who were enrolled at the Northern California site of the Breast Cancer Family Registry during the period 1996-2005. Race/ethnicity and religious ancestry were based on self-report. Weighted estimates of prevalence and 95% confidence intervals (CIs) were based on Horvitz-Thompson estimating equations. MAIN OUTCOME MEASURE Estimates of BRCA1 prevalence. RESULTS Estimates of BRCA1 prevalence were 3.5% (95% CI, 2.1%-5.8%) in Hispanic patients (n = 393),
1.3% (95% CI, 0.6%-2.6%) in African American patients (n = 341),
and 0.5% (95% CI, 0.1%-2.0%) in Asian American patients (n = 444),
compared with 8.3% (95% CI, 3.1%-20.1%) in Ashkenazi Jewish patients (n = 41) and 2.2% (95% CI, 0.7%-6.9%) in other non-Hispanic white patients (n = 508). Prevalence was particularly high in young (<35 years) African American patients (5/30 patients 16.7%;
95% CI, 7.1%-34.3%). 185delAG was the most common mutation in Hispanics,
found in 5 of 21 carriers (24%). CONCLUSIONS Among African American, Asian American, and Hispanic patients in the Northern California Breast Cancer Family Registry, the prevalence of BRCA1 mutation carriers was highest in Hispanics and lowest in Asian Americans. The higher carrier prevalence in Hispanics may reflect the presence of unrecognized Jewish ancestry in this population.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ...ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.
Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.
We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval CI = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).
Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. ...We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.
Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.
One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.
Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.
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