Natural history and age at onset of hereditary breast cancer.

Hereditary breast cancer (HBC) is noteworthy for certain unique facets of its natural history and heterogeneity. Interfamily heterogeneity in age at initial breast cancer diagnosis was investigated in 217 family members with HBC. The mean age at diagnosis was 44.9 years (standard deviation +/- 12.5 years). A one-way analysis of variance in ages at diagnosis, using the family as a random effect factor, indicated that between-family differences were significant (P less than 0.002) and accounted for approximately 18% of the variance in ages at diagnosis. A subset of families with HBC was characterized by an extraordinarily early onset of breast cancer. A knowledge of the natural history of HBC with particular attention to age at onset allows for the development of more accurately targeted surveillance, genetic counselling, and management strategies.     

CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers

The polymorphic genetic differences among individuals may modify the high risk for breast cancer (BC) and/or ovarian cancer (OC) susceptibility conferred by BRCA1 and BRCA2 mutations. In the present study we investigate the relevance of RAD51 ?135C > G, TP53 R72P, NQO1*2 and CASP8 D302H polymorphisms as potential modifiers of BC and/or OC susceptibility conferred by these mutations. The study group encompasses 390 BRCA1/BRCA2 mutation carriers (182 affected with BC and/or OC and 208 unaffected) of 131 unrelated families studied in the Program of Genetic Counselling on Cancer of Valencia Community. The polymorphisms were detected in genomic DNA by ASRA method or real time PCR using fluorescently labeled probes. We found similar incidence of RAD51 ?135C > G, TP53 R72P and NQO1*2 polymorphisms among affected and unaffected individuals considering BRCA1/BRCA2 mutations together and separately. However, the CASP8 D302H polymorphism was strongly associated with the absence of BC [OR = 3.41 (95% CI 1.33–8.78, P = 0.01)]. In fact, in the females with CASP8 D302H polymorphism the BC appeared at a median age of 58 in opposition to the 47 years observed for the wild type subjects (P = 0.03). Furthermore, the CASP8 D302H positive females showed a 50% probability of being free of BC by the age of 78 versus the 2% of the CASP8 negative ones. Our results support that the presence of the CASP8 D302H polymorphism diminishes the high risk of BC conferred by BRCA1 and BRCA2 mutations, making possible that some of the carriers could escape from suffering BC along their life span.     

CCND1 polymorphism and age of onset of hepatoblastoma

Cyclin D1, encoded by the gene CCND1, is a major regulator of the cell cycle transition from G1 phase to S phase. A CCND1 polymorphism (G to A) at codon 242, the boundary of exon 4 and intron 4, affects splicing such that exon 5 is not expressed in the A allele. Since exon 5 is involved in rapid turnover, the variant cyclin D1 corresponding to the A allele may have a longer half-life. A previous study demonstrated that in families with hereditary nonpolyposis colorectal cancer, the age of onset of colorectal cancer varied according to variation at this polymorphic site. We examined this CCND1polymorphism in a series hepatoblastoma, a childhood liver cancer that shares other molecular features with colon cancer. We determined in an analysis of 84 children with hepatoblastoma that the G/A exon 4 polymorphism in CCND1 is correlated with the age of onset of hepatoblastomas. The A/A genotype is associated with an earlier age of onset compared to the G/A or G/G genotype. The median age of patients with the G/G genotype was 22 months, compared to 17 months in patients with the G/A genotype and 11 months for the A/A genotype. These findings suggest that the CCND1 A polymorphism may contribute to tumor development in children with hepatoblastoma.     

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors

Background  

Findings from previous studies regarding the association between the CYP17 genotype and breast cancer are inconsistent. We investigated the role of the MspAI genetic polymorphism in the 5' region of CYP17 on risk of breast cancer and as a modifier of reproductive risk factors.     

Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer

BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary breast cancer. In the actuarial outcomes after 10 years' follow-up, 40% of the 124 BRCA1-patients diagnosed with breast cancer < 50 years had developed contralateral breast cancer, vs 12% of the 40 patients > 50 years at first diagnosis (Plogrank = 0.02). These data suggest that age at diagnosis of the first tumour should be taken into account when prophylactic mastectomy in BRCA1-patients is considered.     

Chromosomal radiosensitivity in breast cancer patients: influence of age of onset of the disease

The age dependency of onset of the disease on chromosomal radiosensitivity of an unselected group of breast cancer patients (n=100) was investigated and compared to a group of healthy women (n=100). The chromosomal radiosensitivity was assessed with the G2 and the G0 micro-nucleus (MN) assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy 60Co gamma-rays after 70 h incubation and chromatid breaks were scored in 50 metaphases. For the G0 MN assay lymphocytes were exposed in vitro to 3.5 Gy 60Co gamma-rays at low dose rate (LDR). 72 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients was more radiosensitive than a population of healthy women and this with both the G2 and the G0 MN assay. Analyses of the G2 and MN response in different age groups of the breast cancer patients revealed no significant differences in mean G2 and MN scores and suggest that the age of onset of the disease has no effect on chromosomal radiosensitivity in unselected breast cancer patients. Correlations with different clinical parameters were also investigated.     

PALB2基因遗传多态性在早发性乳腺癌中的作用

背景与目的:PALB2基因是新近发现的乳腺痛易感基因,其多个遗传单核苷酸多态性(SNP)可能与乳腺癌发病风险有关,本研究探讨PALB2基因rs249954、rs447529及rs16940342多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性.方法:对124例早发性乳腺癌患者(年龄≤35岁)和101例健康女性进行PALB2基因rs249954、rs447529及rs16940342 PCR扩增,并采用基质辅助激光解吸电离飞行时间质谱分析(MALDI-TOF-MS)法鉴定其基因型,比较各基因型分布和发病风险的关系;应用非条件Logistic回归分析计算危险度(OR)及95%CI.结果:PALB2基因rs249954、rs447529及rs16940342多态性基因型在病例组中的分布频率与对照组的分布频率均未见明显差异(P＞0.05).Logistic回归分析表明,在早发性乳腺癌人群中,以rs249954的CC基因型、rs447529 CC基因型及rs16940342 AA基因型为参照,各基因多态性位点的其他基因型,均未能显著改变乳腺癌的发病危险(P＞0.05).各基因型风险比分别为1.061(rs249954 TT vs CC),0.793(rs447529 GG vs CC)以及0.921(rs16940342 GG vs AA).结论:PALB2基因rs249954、rs447529及rs16940342多态性可能与福建地区汉族人群早发性乳腺癌的遗传易感性无关,作为低外显率的乳腺癌易感基因位点和未来临床基因筛查的候选指标尚需谨慎.     

Expression of sulfotransferases and sulfatases in human breast cancer: Impact on resveratrol metabolism

Resveratrol is a naturally occurring anticancer compound present in grapes and wine that undergoes pronounced metabolism in human intestine and liver. In order to determine whether resveratrol is also bio-transformed in human breast carcinoma, metabolism experiments were conducted in breast tumor and adjacent non-tumorous specimens from 13 patients. Resveratrol was metabolized in cytosolic tissue fractions to resveratrol-3-O-sulfate: the formation rates were up to 33.5-fold higher in cancer samples than in peritumoral tissue. Further quantitative real-time RT-PCR analysis revealed similar expression of sulfotransferases SULT1A2, 1A3, and 1E1 in the paired control and tumor tissues. Sulfotransferase SULT1A1 expression was below the detection limit in all samples. Interestingly, mRNA expression of steroid sulfatase STS, but not of arylsulfatases ARS-A and ARS-B, was significantly higher (p < 0.0017) in non-malignant specimens than in tumor tissue samples, which might explain the higher resveratrol-3-O-sulfate concentrations in breast cancer specimens. Cellular localization of SULT1A3 and STS was also assessed by indirect immunofluorescence on paraffin-embedded sections from control and malignant breast tissue clearly showing a correlation of qRT-PCR data with protein expression of these two enzymes. Our data elucidate the metabolism of resveratrol in malignant and non-malignant breast tissue, which must be considered in humans after oral uptake of dietary resveratrol as a chemopreventive agent.     

The hormonal basis of breast cancer

Both animal experiments and certain well-established breast cancer risk factors suggest that risk to the disease is fundamentally determined by the hormones of the pituitary-gonadal axis. Although international comparisons of urinary estrogens have given support to this ypothesis, case-control studies and international comparisons of plasma estrogens and prolactin have not. Methodological problems and sampling biases probably account for the inconsistency of these investigations. Taking advantage of the known familial increased risk to breast cancer, we conducted comparative studies of teenage daughters of patients with breast cancer, including a group of girls whose mothers had bilateral breast cancer when they were less than 50 years old. The results of these studies revealed that these high-risk girls appear to have elevated levels of estrogens, prolactin, and progesterone.     

Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer

A common polymorphism in the cyclin D1 gene enhances the gene's alternate splicing. The alternatively spliced product encodes an altered protein that does not contain sequences involved in the turnover of the protein. We found that hereditary nonpolyposis colorectal carcinoma patients who were homozygous or heterozygous for the mutant allele developed colorectal cancer an average of 11 years earlier than patients who were homozygous for the normal alleles. This is the first report indicating that the cyclin D1 polymorphism influences age of onset of cancer. Because cyclin D1 plays an important role in the G1 to S phase transition of the cell cycle, our findings suggest that cells with the mutant allele accumulate mutations as a result of defective mismatch repair and may also bypass the G1-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. The polymorphism has a dominant phenotype.     

Family history and age at onset of breast cancer in Hispanic and non-Hispanic white women

Objectives  To evaluate the association between family history of breast cancer and breast cancer risk among Hispanic and non-Hispanic white (NHW) women. Methods  Logistic regression models were used to compute unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using data collected from the 4-Corners Breast Cancer Study, a population-based case–control study of breast cancer conducted in the Southwest United States (3,074 NHW and 1,647 Hispanic women). Results  The association between family history of breast cancer and early-onset breast cancer risk differs among NHW and Hispanic women. Among women <50 years old, having a family history of breast cancer was associated with a greater increase in risk among NHWs, with an OR of 2.34 (95% CI: 1.64–3.35) when compared to an OR of 1.32 (95% CI: 0.82–2.19) for Hispanics. This difference in risk was not observed among women 50 years and older, with an OR of 1.69 (95% CI: 1.34–2.13) for NHW and 1.47 (95% CI: 1.03–2.10) for Hispanics. Conclusions  Family history of breast cancer poses a greater risk for early-onset breast cancers among NHW when compared to Hispanic women and may reflect ethnic differences in certain predisposing genetic factors that promote breast cancer development.     

Increased urinary androgen excretion is a hormonal abnormality detectable before the clinical onset of breast cancer

Six patients who developed breast cancer between the ages of 27 and 55 years had been examined for their urinary excretion of testosterone and androstanediol 17 to 69 months before the clinical onset of their cancer. Each of them showed higher than normal excretion values of testosterone or androstanediol, or both. At the time of hormonal examination, the patients were considered at risk for breast cancer because their history had included one or more of the following factors: previous mammary disease, familiality, sterility or subfertility, menstrual cycle irregularities. On the basis of this evidence, it would seem that high androgenic activity is a risk factor for developing breast cancer in patients with the "adverse" history.     

Family history of breast cancer,age and benign breast disease

A major risk factor for breast cancer is having a first-degree family history of the disease. Benign breast disease (BBD), particularly atypical hyperplasia, is also associated with an increased risk of breast cancer. However, the relationship between family history of breast cancer and BBD is unclear. From 1989 through 1997, 80,995 participants in the Nurses' Health Study II were followed; 16,849 reported a first diagnosis of BBD. Pathology slides were reviewed for 1,465 women who reported having a tissue biopsy, and these were classified as nonproliferative BBD, proliferative BBD without atypia or atypical hyperplasia. Women with a family history of breast cancer were more likely to report a physician diagnosis of BBD [rate ratio (RR) = 1.38, 95% confidence interval (CI) 1.29-1.46]. The magnitude of this association declined with age from RR = 1.96 (95% CI 1.55-2.47) at 25-29 years to RR = 1.20 (95% CI 0.95-1.52) at age 45-50 years. Among women with proliferative disease, those with a family history of breast cancer were almost 3 times as likely to have atypia (prevalence odds ratio = 2.72, 95% CI 1.23-5.89) than those with no family history. In conclusion, women with a family history of breast cancer appear to be at increased risk of being diagnosed with BBD, in particular the high-risk types of BBD associated with a greatly increased risk of breast cancer. This link adds weight to the belief that BBD with atypia is a precursor or marker lesion for breast cancer.     

Proven non-carriers in BRCA families have an earlier age of onset of breast cancer

BackgroundRisk estimates for proven non-carriers in BRCA mutation families are inconsistent for breast cancer and lacking for ovarian cancer. We aimed to assess the age-related risks for breast and ovarian cancer for proven non-carriers in these families.MethodsA consecutive cohort study ascertained 464 proven non-carriers who had a first-degree relative with a pathogenic BRCA mutation. Kaplan–Meier analyses were used to estimate the age-related cancer risks, and we calculated standardised incidence ratios.ResultsIn the 464 non-carriers, 17 breast cancers and two ovarian cancers were detected at a mean age of 47 years (95% confidence interval (CI) 32–61) and 49 years (95% CI 32–67), respectively. Overall, by the age of 50, the breast and ovarian cancer risks among non-carriers were 6.4% (95% CI 2.9–9.8%) and 0.4% (95% CI 0–1.3%), of which the breast cancer risk was statistically significantly higher than the risk in the general population. In particular, the number of breast cancers among non-carriers in BRCA1 families was higher than expected for the general population (standardised incidence ratio (SIR) 2.0, 95% CI 1.1–3.3). In the BRCA1 cohort, the mean number of breast cancer cases was higher in families in which non-carriers were diagnosed before the age of 50 (p = 0.04).ConclusionThe age at diagnosis of breast cancer in non-carriers in BRCA mutation families is younger than expected, yielding an increased risk in the fifth decade. This effect is most evident in BRCA1 families. If our results are confirmed by others, this could affect the advice given on breast cancer screening to proven non-carriers between the age of 40 and 50 in such families.     

p53 polymorphism and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies. Colorectal and endometrial cancers are most frequently observed. The syndrome results mainly from germ-line mutations in DNA mismatch repair genes. A common G-to-C polymorphism at codon 72 in the p53 gene has been associated with increased risk for lung, nasopharyngeal, oral, prostate, and breast cancers and may be a marker for genetic susceptibility to colorectal cancer. We studied the influence of this p53 polymorphism on HNPCC age of onset. EXPERIMENTAL DESIGN: We determined the p53 genotype of 92 Caucasian mismatch repair mutation carriers, of which, 47 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism analysis. We tested the association between age of onset and the p53 genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon's test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors. RESULTS: The HNPCC patients who were heterozygous developed their colorectal cancer 13 years earlier than HNPCC patients who were homozygous for the wild-type allele. CONCLUSIONS: Combining knowledge of an individual's p53 genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.