ABO blood type has been associated with risk and survival for several malignancies; however, data for an association with breast cancer are inconsistent. Our study population consisted of Nurses' ...Health Study participants with self‐reported serologic blood type and/or ABO genotype. Using Cox proportional hazards regression, we examined the association between serologic blood type and incident breast cancer among 67,697 women, including 3,107 cases. In addition, we examined the association with ABO genotype in a nested case‐control study of 1,138 invasive breast cancer cases and 1,090 matched controls. Finally, we evaluated the association between serologic blood type and survival among 2,036 participants with breast cancer. No clear association was seen between serologic blood type or ABO genotype and risk of total breast cancer, invasive breast cancer or breast cancer subtypes. Compared to women with blood type O, the age‐adjusted incidence rate ratios for serologic blood type and total breast cancer were 1.06 (95% CI, 0.98–1.15) for type A, 1.06 (95% CI, 0.93–1.22) for AB and 1.08 (95% CI, 0.96–1.20) for B. In genetic analyses, odds ratios for invasive breast cancer were 1.05 (95% CI, 0.87–1.27) for A/O, 1.21 (95% CI, 0.86–1.69) for A/A, 0.84 (95% CI, 0.56–1.26) for A/B, 0.84 (95% CI, 0.63–1.13) for B/O and 1.17 (95% CI, 0.35–3.86) for B/B, compared to O/O. No significant association was noted between blood type and overall or breast cancer‐specific mortality. Our results suggest no association between ABO blood group and breast cancer risk or survival.
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 ...controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining ...the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all P(trend) > or = 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (P(trend) = 0.04) and estrone sulfate (P(trend) = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (P(trend) = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (P(trend) = 0.001), free estradiol (P(trend) = 0.01), estrone sulfate (P(trend) = 0.03), and the ratio of estradiol to testosterone (P(trend) = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users.
Abstract
Phylogeographical patterns of trees in topographically subdued, unglaciated landscapes are under-reported, and might reflect population persistence and the influences of environment and ...distance over historical (~2.6 Mya to present) and contemporary (recent generations) timescales. We examined this hypothesis using genetic analyses of four slowly evolving non-coding chloroplast sequences and 16 nuclear microsatellites in the tree Corymbia calophylla from south-western Australia, an area that has been unglaciated since the Permian (c. 300–250 Mya). We found strong population differentiation for chloroplast DNA and low differentiation for nuclear loci, consistent with higher gene flow by pollen than by seed. We identified three divergent chloroplast lineages distributed in central, northern and southern regions, and diversifying from the early (c. 3.028 Mya), mid- (c. 0.793 Mya) and late (c. 0.426 Mya) Pleistocene, respectively. Moderate to high nucleotide diversity with population-specific haplotypes supported long-term persistence, but diversification of lineages provided evidence of unexpected episodic range expansion. We suggest this pattern reflects environmental influences of climatic oscillations during progressive drying of south-western Australia from the early Pleistocene. Significant tests for isolation by environment for nuclear loci also supported an influence of contemporary environmental (aridity) conditions on genetic structure, but isolation by distance (IBD) was greater. Significant chloroplast and nuclear IBD suggested distance was a major influence on gene flow at both timescales.
Epidemiologic evidence suggests a possible association between genital use of talcum powder and risk of epithelial ovarian
cancer; however, the biological basis for this association is not clear. We ...analyzed interactions between talc use and genes
in detoxification pathways glutathione S-transferase M1 ( GSTM1 ), glutathione S-transferase T1 ( GSTT1 ), and N-acetyltransferase 2 ( NAT2 ) to assess whether the talc/ovarian cancer association is modified by variants of genes potentially involved in the response
to talc. Our analysis included 1,175 cases and 1,202 controls from a New England-based case-control study and 210 cases and
600 controls from the prospective Nurses' Health Study. We genotyped participants for the GSTM1 and GSTT1 gene deletions and three NAT2 polymorphisms. We used logistic regression to analyze the main effect of talc use, genotype, and gene-talc interactions in
each population and pooled the estimates using a random-effects model. Regular talc use was associated with increased ovarian
cancer risk in the combined study population (RR, 1.36; 95% CI, 1.14-1.63; P trend < 0.001). Independent of talc, the genes examined were not clearly associated with risk. However, the talc/ovarian cancer
association varied by GSTT1 genotype and combined GSTM1/GSTT1 genotype. In the pooled analysis, the association with talc was stronger among women with the GSTT1 -null genotype ( P interaction = 0.03), particularly in combination with the GSTM1 -present genotype ( P interaction = 0.03). There was no clear evidence of an interaction with GSTM1 alone or NAT2 . These results suggest that women with certain genetic variants may have a higher risk of ovarian cancer associated with
genital talc use. Additional research is needed on these interactions and the underlying biological mechanisms. (Cancer Epidemiol
Biomarkers Prev 2008;17(9):2436–44)
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from ...blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
Abstract
BACKGROUND: Posterior fossa ependymoma (PF EPN) is a pediatric central nervous system malignancy that has a poor outcome to standard therapeutic approaches. The majority of PF EPN have been ...shown to harbor increased HER2 expression, making it a logical therapeutic target. Trastuzumab is a monoclonal antibody that targets HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor cell proliferation. The combination of trastuzumab and GM-CSF has been shown to trigger antibody-dependent cell cytotoxicity in-vitro in patient-derived PF EPN cell lines. METHODS: Children aged 1–21 years with relapsed PF EPN, no ventriculoperitoneal shunt, and no CSF obstruction are eligible for the Phase 0/I single-institution clinical trial at Children’s Hospital Colorado. Stratum 1 involves intrathecal (IT) trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-care surgical resection. Stratum 2 involves a 3 + 3 phase I design with serial IT trastuzumab doses, each preceded by three days of GM-CSF, to establish the maximum tolerated dose for IT trastuzumab. RESULTS: Trastuzumab was detected in a sufficient number of tumors after presurgical IT delivery in Stratum 1 to open Stratum 2. Seven patients (3 female) have been enrolled in Stratum 2. Median age at enrollment is 8.1 years (range, 3–20 years). CSF pharmacokinetic analysis demonstrate detectable trastuzumab up to 14 days after IT doses. No dose-limiting toxicities or grade 3 or 4 adverse events have occurred. Four patients completed all planned study therapy and remain progression-free post-therapy (median, 23 months, range, 6-42 months). Three patients progressed on therapy (median, 4 cycles). Biologic correlative studies are in process. CONCLUSIONS: IT trastuzumab penetrates PF EPN tumor tissue and demonstrates an excellent safety profile. Stratum 2 remains open to accrual at Dose Level 2. IT trastuzumab+GM-CSF warrants consideration for a multi-institutional Phase II trial.
Several studies have reported a positive association between perineal use of talcum powder among adult women and ovarian cancer risk. However, the relationship between talcum powder use and other ...gynecologic malignancies such as endometrial cancer has not been examined, and little information is available on nonhormonal risk factors for endometrial cancer.
Perineal use of talcum powder was assessed in 1982 in the Nurses' Health Study. Approximately 40% of women who responded to the questions about perineal use of talcum powder reported ever use. Cox proportional hazards models were used to estimate the incidence rate ratio of endometrial cancer and 95% confidence interval (CI), adjusted for body mass index and other potential confounders. We evaluated the relationship among all women and stratified by menopausal status.
Our analysis included 66,028 women with 599 incident cases of invasive endometrial adenocarcinoma diagnosed between 1982 and 2004. Although no association was observed overall, the association varied by menopausal status (P interaction=0.02) and a positive association was observed among postmenopausal women; ever use of talcum powder was associated with a 21% increase in risk of endometrial cancer (95% CI, 1.02-1.44), whereas regular use (at least once a week) was associated with a 24% increase in risk (95% CI, 1.03-1.48). In addition, we observed a borderline increase in risk with increasing frequency of use (P trend=0.04).
Our results suggest that perineal talcum powder use increases the risk of endometrial cancer, particularly among postmenopausal women.
Future and larger studies are needed to confirm this association and investigate potential mechanisms.
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.
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