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Biomedical subjects

D F Easton

Publications and source records attributed to D F Easton.

At least 37 records · Page 2Linked to original sources
PubMed2001

CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97-1.17) for BC and 1.00 (95%CI 0.83-1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80-1.15) and 0.90 (95%CI 0.60-1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case-control series were 1.00 (95%CI 0.91-1.10) for the CAG and 1.05 (95%CI 0.90-1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with > or =28 CAG repeats was 1.08 (95%CI 0.45-2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak.

Adult↗
PubMed2001

Apparent human BRCA1 knockout caused by mispriming during polymerase chain reaction: implications for genetic testing.

We report an apparent BRCA1 homozygous knockout that, on further analysis, was found to be an artefact of the polymerase chain reaction. This finding has two important implications. First, it challenges results of a previous study that reported a homozygous knockout associated with the same BRCA1 mutation. Second, our findings suggest that mispriming caused by mismatched primers at the site of single-nucleotide polymorphisms, leading to preferential amplification of one allele, may represent a significant proportion of instances of mutation-detection insensitivity. This may have major implications for the sensitivity of all polymerase chain reaction-based mutation-detection methods in clinical genetic testing laboratories.

Artifacts↗
PubMed2001

Polymorphisms in CYP1A1 and smoking: no association with breast cancer risk.

Several studies have investigated polymorphisms in CYP1A1 and breast cancer risk with inconsistent results. We have carried out a population based case-control study of the Thr461Asn and Ile462Val polymorphisms in CYP1A1 to clarify their importance in determining breast cancer susceptibility. A total of 1873 cases and 712 controls were genotyped for Thr461Asn and 1948 cases and 1355 controls were genotyped for Ile462Val. We have also investigated a putative interaction between smoking and CYP1A1 genotype and breast cancer risk using a case only study design. The genotype distribution of Thr461Asp in controls was close to that expected under Hardy-Weinberg equilibrium (HWE). We detected no significant differences in genotype frequencies between breast cancer cases and controls (P = 0.68). Compared with the Thr/Thr homozygotes there was no significant risk for either the Thr/Asp heterozygote [OR = 1.1 (95% CI 0.8-1.4)] or the Asp/Asp homozygote [OR = 0.4 (0.02-6.1)]. The genotype distribution of Ile462Val in controls was also close to that expected under HWE with no significant differences between breast cancer cases and the controls (P = 0.44). No significant risk was found for either the Ile/Val heterozygote [OR = 0.8 (0.6-1.1)] or the Val/Val homozygote [OR = 2.7 (0.3-24)] compared with the Ile/Ile homozygotes. Furthermore, subgroup analyses revealed no effect of age or menopausal status on genotypic risks, and we found no evidence for an interaction between genotype and smoking habit or alcohol consumption and susceptibility to breast cancer. We combined our data for the Ile462Val polymorphism with those from four other published studies, but even with >5000 subjects, none of the genotype-associated risks achieved statistical significance, and there was no consistent pattern to the risks associated with increasing Val allele dosage [Ile/Val OR = 0.9 (0.7-1.1), Val/Val OR = 2.3 (0.4-12), and Val carrier OR = 1.0 (0.9-1.1)].

Aged↗
PubMed2000

After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer.

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years, ascertained through population cancer registries in Melbourne and Sydney, Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes.

Age Factors↗
PubMed2000

CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

BACKGROUND: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed. RESULTS: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years. CONCLUSIONS: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.

Adult↗
PubMed2000

Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22.

Several recent studies indicate that the majority of families with five or fewer cases of breast cancer and no cases of ovarian cancer are not due to BRCA1 or BRCA2. It has been proposed that a further breast cancer susceptibility gene that may account for some of these families is located on chromosome 8p12-p22. We have identified 31 site-specific breast cancer families that have a greater than 80% posterior probability of being due to genes other than BRCA1 or BRCA2. These families have been examined for linkage to 8p12-p22 using markers flanking the putative location of the gene. The overall multi-point LOD score is strongly negative across the whole 44 cM. The individual multi-point LOD score is negative in 23 families and only exceeds 0.5 in a single family (with a multi-point LOD score of 1.22). The maximum heterogeneity LOD score was 0.03 at marker D8S136 with estimated proportion linked (alpha) of 3% (95% CI 0 - 30%). These data do not lend support to the hypothesis that chromosome 8p12-p22 harbours a familial breast cancer susceptibility gene. Oncogene (2000) 19, 4170 - 4173

BRCA2 Protein↗
PubMed2000

The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Adult↗
PubMed2000

Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer.

There are few published estimates of the risk of developing breast or ovarian cancer in women with a strong family history of ovarian cancer. As these women commonly present to family cancer clinics, accurate cancer risk estimates are needed. We have estimated these risks in women from families with 2 or more confirmed ovarian cancers in first-degree relatives using data from the UKCCCR Familial Ovarian Cancer Register. The number of cancers observed in more than 10,000 person years of follow-up was compared with the number expected based on national-, age-, sex- and period-specific incidence rates. The relative risk of ovarian cancer was found to be 7.18 (95% CI 3.82-12.3), declining from 16.0 (6.40-32.9) in women under 50 to 4.38 (1.60-9.52) in women 50 years of age and older. For breast cancer, the relative risk for women under 50 was 3.74 (2.04-6. 28) and 1.79 (1.02-2.90) for women 50 years of age and older (average RR 2.36, 1.59-3.37). These correspond to absolute risks by age 70 of 11% for ovarian cancer and 15% for breast cancer. When the analyses were restricted to families that had been negative for mutations in the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2, the ovarian cancer risk was 11.59 (3.12-29.7) and that of breast cancer 3.32 (1.52-6.31). As well as having clinical relevance, our finding may suggest that other breast/ovarian cancer genes are segregating in these families, though the possibility of undetected BRCA1/2 mutations must also be considered.

Age Factors↗
PubMed2000

Risk models for familial ovarian and breast cancer.

We investigated risk models for the inherited susceptibility of breast and ovarian cancer, using data from both high-risk families and a population based series of ovarian cancer. The first data set consisted of 112 families containing two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. The second study involved 374 ovarian cancer cases, unselected for family history, who had DNA samples analyzed for BRCA1 mutations. Twelve women were found to be carriers. We constructed genetic models for ovarian and breast cancer using the computer program MENDEL. In the first study, we modeled the effects of BRCA1 and BRCA2 simultaneously and allowed for a third gene predisposing to ovarian cancer. None of the models fitted gave significant evidence for a third gene. Population frequencies of BRCA1 and BRCA2 mutations were estimated to be 0. 00128 and 0.00172, respectively. Our results suggest that BRCA1 and BRCA2 may be sufficient to explain the majority of familial ovarian cancer and that families without mutations can be explained by sensitivity of mutation testing and chance clusters of sporadic cases. Using data on the families of the 12 mutation carriers in the second study, we estimated age-specific ovarian and breast cancer risks for BRCA1 mutation carriers. Under the best-fitting model, the cumulative ovarian cancer risk was 66% by age 70, and the corresponding breast cancer risk was 45%. The high penetrance estimate for ovarian cancer, compared with other studies, suggests that modifying genetic or environmental factors may be important determinants of risk.

Breast Neoplasms↗
PubMed2000

Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease.

Genetic linkage analysis in families with multiple cases of inflammatory bowel disease (IBD) has mapped a gene which confers susceptibility to IBD to the pericentromeric region of chromosome 16 (IBD1). The linked region includes the interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are abnormal in IBD, the IL4R gene is thus both a positional and functional candidate for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with IBD in 355 families, which included 435 cases of Crohn's disease and 329 cases of ulcerative colitis. No association was observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) and either the Crohn's disease or ulcerative colitis phenotypes using the transmission disequilibrium test. There was also no evidence for association when the four markers were analyzed individually. The results indicate that these variants are not significant genetic determinants of IBD, and that the IL4R gene is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants are in complete equilibrium with each other, although they are separated by only about 21 kilobases of genomic DNA. This suggests that a very dense SNP map may be required to exclude or detect disease associations with some candidate genes.

Alleles↗
PubMed2000

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study. UK MRI Breast Screening Study Advisory Group.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

Adult↗
PubMed2000

Familial predisposition to breast cancer in a British population: implications for prevention.

The aims of this study were to estimate the familial relative risk of breast cancer according to the age of the at risk individual and the age at which the relative was affected, and to estimate the proportion of the general population in several breast cancer risk categories because of a family history and, thus estimate the potential to reduce the overall breast cancer burden using interventions targeted at women at increased risk because of family history. Familial relative risks were computed by comparing breast cancer incidence in relatives of 2809 breast cancer cases from a population based case series with that expected from general population incidence rates. The proportion of the general population in different categories of risk according to family history was estimated from the relative risk of breast cancer for that category and the proportion of cases in that category. 389 (13.8%) cases had at least 1 first degree relative with breast cancer. The relative risk of breast cancer in sisters of index cases was 1.90 (95% confidence interval (CI) 1.63-2.36) and that in mothers 1.73 (1.52-1. 97). The risk to mothers of cases diagnosed under 50 years of age tended to decrease in older mothers, but no age effect was seen for mothers of cases diagnosed >/=50 years of age. There was no evidence that relative risk to sisters declined with age. For women with 2 affected first degree relatives the relative risk was 2.85 (2.12-3. 76). From these data, we estimate that in the general population 6. 8% of women under the age of 50 years and 9.7% of women aged 50-65 years have at least 1 first degree relative affected with breast cancer. Two per cent of women under 50 years have a family history which confers an increased risk of at least 2.5-fold. An intervention targeted at this group that reduced breast cancer morbidity by 20% would reduce the total burden of breast cancer in this age group by 1.1% at most. A family history of breast cancer is quite common in the general population, but preventive interventions targeted at women at high risk of breast cancer because of family history will have limited impact on breast cancer morbidity as a whole.

Adult↗
PubMed2000

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Adolescent↗
PubMed2000

A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

Alleles↗
PubMed2000

Rationale for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study.

Journal Article↗
PubMed2000

Protocol for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

Journal Article↗
PubMed2000

Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast cancer risk.

The aromatase enzyme catalyses the conversion of androgens to oestrogens in the oestrogen biosynthesis pathway. Because increased exposure to oestrogens is considered to be a risk factor for breast cancer, the human aromatase gene (CYP19) is a plausible candidate for low penetrance breast cancer susceptibility. Preliminary reports have suggested that specific alleles of a TTTA repeat may be associated with differences in breast cancer risk. We have identified two new polymorphisms in the CYP19 gene: a TCT insertion/deletion in intron 4 and a G-->T substitution in intron 6, which have rare allele frequencies of 0.35 and 0.45, respectively, in the British population. Comparison was made between the frequencies of these alleles and those of the TTTA repeat in up to 599 breast cancer cases and 433 normal controls from the East Anglian, British population. We found strong linkage disequilibrium between the alleles of these three loci, but no significant association of any alleles with breast cancer risk. The maximum odds ratios observed were: 1.03 (95% CI 0.68-1.55) for the intron 4 TCT insertion/deletion polymorphism [del/del versus ins/ins]; 1.56 (95% CI 0.63-3.83) for the intron 4 [TTTA](10) allele; 1.29 (95% CI 0. 75-2.21) for the intron 6 G-->T polymorphism [TT versus GG]. We conclude that the CYP19 gene has no major role in common breast cancer incidence in the British population.

Adult↗