Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We ...hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78–5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age–phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. Accession numbers: The microarray data and associated .BED and .WIG files can be accessed through Gene Expression Omnibus accession number: GSE14603.
Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in ...HPV positive women.
Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection.
28 eligible studies were identified, together including 12 531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5–9 years, and 10 or more years, respectively, the summary relative risks were 1·1 (95% CI 1·1–1·2), 1·6 (1·4–1·7), and 2·2 (1·9–2·4) for all women; and 0·9 (0·7–1·2), 1·3 (1·0–1·9), and 2·5 (1·6–3·9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results.
Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.
Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally ...considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls. Twenty-five of these SNPs were in BRCA1, BRCA2, ATM, TP53 and CHEK2. Among the 1037 SNPs there were a few significant findings, but hardly more than would be expected in this large experiment. There was, however, a significant trend in risk with increasing numbers of variant alleles for the 25 SNPs in BRCA1, BRCA2, ATM, TP53 and CHEK2 (Ptrend = 0.005). For the 21 of these with minor allele frequency <10% this trend was highly significant (Ptrend = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% CI 1.69–4.97). The individual effects of most of these risk alleles were undetectably small even in this well powered study, but the risk conferred by multiple variants is readily detectable and makes a substantial contribution to susceptibility. A risk score incorporating a suitably weighted sum of all potentially functional variants in these and a few other candidate genes may provide clinically useful identification of women at high genetic risk.
We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF)
and their binding proteins (IGFBP), polymorphisms in their genes, and ...breast cancer risk. In premenopausal women, five of
eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more
than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at
young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5′
to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no
convincing evidence of any effect. For an A/C polymorphism 5′ to IGFBP-3 , all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast
cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only
modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation.
Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants
could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these
effects more precisely.
Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of ...494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment=0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend=0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI.
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