Mammographic densities are hypothesized to reflect the cumulative exposure to risk factors that influence breast cancer incidence.
This report analyzed percent densities over time and explored ...predictors of density change in relation to age. The study population
consisted of 607 breast cancer cases and 667 frequency matched controls with 1,956 and 1,619 mammographic readings, respectively.
Mammograms done over >20 years and before a diagnosis of breast cancer were assessed for densities using a computer-assisted
method. Using multilevel modeling to allow for repeated measurements, we estimated the effect of ethnicity, case status, reproductive
characteristics, hormonal therapy, body mass index, and soy intake on initial status and longitudinal change. After integrating
the area under the percent density curve, cumulative percent density was compared with age-specific breast cancer rates in
Hawaii. Percent densities decreased ∼5.6% per 10 years but a nonlinear effect indicated a faster decline earlier in life.
Cumulative percent densities and age-specific breast cancer rates increased at very similar rates; both standardized regression
coefficients were >0.9. Japanese ancestry, overweight, estrogen/progestin treatment, and, to a lesser degree, estrogen-only
therapy predicted a slower decline in densities with age. Case status and adult soy intake were related to higher densities
whereas overweight and having any child were associated with lower densities at initial status. Risk factors that influence
the decline in mammographic densities over time may be important for breast cancer prevention because cumulative percent densities
may reflect the age-related increase in breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(4):732–9)
Although the role of estrogen in the etiology of ovarian cancer is uncertain, there is increasing evidence that hormone replacement therapy is a risk factor for ovarian malignancy. The production of ...estrogen involves the conversion of androgens via P450 aromatase, encoded by the CYP19A1 gene. Genetic variation in two CYP19A1 single-nucleotide polymorphisms (SNPs), rs749292 and rs727479, has been found to produce 10–20% increases in estrogen levels among postmenopausal women. We tested the hypothesis that these SNPs were associated with the risk of ovarian cancer in a population-based case–control study in Hawaii, including 367 histologically confirmed epithelial ovarian cancer cases and 602 age- and ethnicity-matched controls. The A allele of rs749292 was positively associated with ovarian cancer risk in a codominant model for all races combined (AG versus AA genotype: odds ratio (OR), 1.48 and 95% confidence interval (CI, 1.07–2.04); GG versus AA: OR, 1.87 (CI, 1.24–2.82); Ptrend=0.002). Similar significant associations of the rs749292 A allele on the risk of ovarian cancer were found among Caucasian and Japanese women. No relation of the rs727479 SNP to ovarian cancer risk was observed overall, although Caucasian women carrying the variant A allele compared with women with an CC genotype had an OR of 2.91 (CI, 1.15–7.37). These data suggest CYP19A1 variants may influence susceptibility to ovarian cancer.
Oxidative stress during successive ovulations increases the opportunity for DNA damage to ovarian epithelial cells and the
potential for malignant transformation. Paraoxonase 1 (PON1) is an ...endogenous free radical scavenger that reduces oxidative
stress. The association of two common functional single nucleotide polymorphisms (SNP), rs854560 T>A and rs662 A>G, with the
risk of epithelial ovarian cancer was examined in a population-based case-control study in Hawaii. A personal interview and
blood specimens were collected from 274 women with histologically confirmed, primary ovarian cancer and 452 controls frequency
matched on age and ethnicity. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic
regression. Both PON1 SNPs were significantly associated with ovarian cancer risk. The ORs were 0.53 (95% CI, 0.35-0.79; P for allele-dose effect = 0.01) for women carrying the rs854560 T allele compared with women with the AA genotype and 0.65
(95% CI, 0.44-0.95; P for allele-dose effect = 0.03) for women carrying the rs662 A allele compared with women with the GG genotype. The association
of the rs854560 T genotype with risk was stronger among smokers (OR, 0.33; 95% CI, 0.17-0.64; P for allele-dose effect = 0.0007) than among nonsmokers (OR, 0.68; 95% CI, 0.40-1.18; P for allele-dose effect = 0.53). The decreased risk associated with the rs854560 T allele was also stronger among obese women
(OR, 0.19; 95% CI, 0.06-0.55; P for allele-dose effect = 0.007) than among nonobese women (OR, 0.62; 95% CI, 0.40-0.98; P for allele-dose effect = 0.16). Our study provides evidence for an association of two PON1 SNPs with the risk of epithelial ovarian cancer. Possible effect modification of these associations by tobacco smoking and
obesity needs confirmation in other studies. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2070–7)
There is evidence that circulating estrogens are associated with breast cancer risk. In this study of premenopausal women,
we explored the association of polymorphisms in genes in the estrogen ...synthesis and metabolism pathways with serum and urinary
levels of estrone (E 1 ) and estradiol (E 2 ) and with the urinary ratio of 2-hydroxyestrone (2-OHE 1 )/16α-hydroxyestrone (16α-OHE 1 ). This analysis included 220 women, who were participants in a 2-year randomized soy intervention. Blood specimens were collected
in the luteal phase of the menstrual cycle an average of 4.4 times over 2 years. Overnight urinary specimens were collected
on the same cycle day, only at baseline. Levels of E 1 , E 2 , 2-OHE 1 , and 16α-OHE 1 were measured by enzyme immunoassays. The DNA samples were analyzed by PCR/RFLP for the COMT Val 158 Met, CYP1A1*2A, CYP1A1*2B, CYP1A2*1F, CYP1B1 Val 432 Leu, and CYP17 T27C polymorphisms. We applied mixed models to investigate the relations between genotypes and repeated serum hormone measurements
and generalized linear models to assess associations between genotypes and urinary estrogen metabolites. The CYP1A2 C allele was significantly associated with lower serum E 2 levels; in CC genotype carriers, serum E 2 levels were 26.3% lower than in homo- and heterozygous common allele carriers combined ( P = 0.01). CYP1A2*1F also affected the urinary 2-OHE 1 /16α-OHE 1 ratio; carriers of the variant C allele had a markedly lower ratio than individuals with the AA genotype (1.37 versus 1.76;
P = 0.002). These data suggest that CYP1A2*1F is associated with lower circulating levels of E 2 , and that it may be a susceptibility locus for breast cancer.
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors ...because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
Summary Background Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We ...undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. Methods Data from 13 ovarian cancer case–control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. Findings 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 20·2% of 674 cases vs 818 6·2% of 13 226 controls, odds ratio 3·05, 95% CI 2·43–3·84, p<0·0001), low-grade serous (31 9·2% of 336 cases, 2·11, 1·39–3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 13·9% of 1220 cases, 2·04, 1·67–2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 6·0% of 516 cases, 1·02, 0·69–1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 7·1% of 3659 cases, 1·13, 0·97–1·32, p=0·13), or borderline tumours of either subtype (serous 103 9·0% of 1140 cases, 1·20, 0·95–1·52, p=0·12, and mucinous 65 8·5% of 767 cases, 1·12, 0·84–1·48, p=0·45). Interpretation Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer. Funding Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in ...breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ...ovarian cancer risk have been inconclusive.
We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.
Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval CI = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91).
Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these ...mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10
), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10
) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Summary Background Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological ...subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. Methods 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. Findings 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21–0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55–0·91; p=0·0080), but weak PR expression was not (1·02, 0·89–1·18; p=0·74). Interpretation PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. Funding Carraresi Foundation and others.
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