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Diana M Eccles

Publications and source records attributed to Diana M Eccles.

15 recordsLinked to original sources
PubMed2026

Updated ENIGMA recommendations for reporting germline variants in cancer susceptibility genes and their translation into twenty languages.

Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers' genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent BRCA1 and BRCA2 specifications to the American College of Medical Genetics and Genomics/Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight country-specific differences in breast cancer risk assessment and management. The updated recommendations and their 20 translations are now provided as easy to handle documents, covering 11 of the most widely spoken languages in the world. They will contribute to minimised erroneous inferences, more informed decision-making, improved health outcomes and equity in the use of genetic testing for cancer predisposition and in translational oncology.

Humans↗
PubMed2026

Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer.

Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1, TP53, FAT1, and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between gBRCA1- and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for gBRCA1 versus gBRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.

Humans↗
PubMed2006

Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers.

BACKGROUND: The MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1. METHODS: Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technologytrade mark was used to determine the genotype at the MDM2 SNP309 locus. RESULTS: The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80). CONCLUSION: We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.

Adolescent↗
PubMed2005

No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer.

A functional T to G germline polymorphism in the promoter region of MDM2 (SNP309) has been reported to profoundly accelerate tumor formation suggesting that it may also represent a powerful cancer predisposing allele. To investigate the role of SNP309 in cancer predisposition we undertook a case-control study of this polymorphism among 351 women diagnosed with breast cancer, 302 women diagnosed with ovarian and 258 female controls from a British population. The GG genotype was not associated with either breast cancer (OR 1.04, 95% CI 0.67-1.60) or ovarian cancer (OR 0.86, 95% CI 0.53-1.37). This study has found no evidence that the GG genotype of the MDM2 SNP309 polymorphism is associated with early onset or familial breast cancer or with ovarian cancer.

Adolescent↗
PubMed2005

Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international Federation of gynecology and obstetrics system.

PURPOSE: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA-125 estimation) in detecting presymptomatic ovarian cancer in women at increased genetic risk. PATIENTS AND METHODS: A cohort of 1,110 women at increased risk of ovarian cancer were screened between January 1991 and March 2004; 553 were moderate-risk individuals (4% to 10% lifetime risk) and 557 were high-risk individuals (> 10% lifetime risk). Outcome measurements include the number and stage of screen-detected cancers, the number and stage of cancers not detected at screening, the number of equivocal screening results requiring recall/repetition, and the number of women undergoing surgery for benign disease. RESULTS: Thirteen epithelial ovarian malignancies (12 invasive and one borderline), developed in the cohort. Ten tumors were detected at screening: three International Federation of Gynecology and Obstetrics (FIGO) stage I (including borderline), two stage II, four stage III, and one stage IV. Of the three cancers not detected by screening, two were stage III and one was stage IV; 29 women underwent diagnostic surgery but were found not to have ovarian cancer. CONCLUSION: Annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis. With a positive predictive value of 17% and a sensitivity of less than 50%, the performance of ultrasound does not satisfy the WHO screening standards. In addition, the combined protocol has a particularly high false-positive rate in premenopausal women, leading to unnecessary surgical intervention.

Adult↗
PubMed2005

A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer.

UNLABELLED: The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. A novel allele was identified which has a tandem duplication of a 13 base pair sequence in the promoter region. METHODS: We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer. RESULTS: The duplication allele had a frequency of 0.34 in the normal controls. There was a non-significant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours. CONCLUSION: The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer.

Adult↗
PubMed2005

Familial non-BRCA1/BRCA2-associated breast cancer.

Multidisciplinary breast-cancer teams commonly encounter women, both premenopausal and postmenopausal, presenting with breast cancer who also have a family history of this disease. Much of the published work on management of hereditary breast cancer focuses on women with known mutations in BRCA1 and BRCA2, in whom high-grade tumours, common second primaries, and a differential response to adjuvant chemotherapies could be relevant in finding the most effective management strategies. Extrapolation of some of these findings to all patients with familial breast cancer is tempting. However, for women in whom BRCA1 or BRCA2 mutations are unlikely or not found, what evidence is there to inform choices about the various management options? We review the published work on management issues for patients with familial breast cancer not due to a detectable mutation in BRCA1/BRCA2 and compare it with the issues for BRCA1 and BRCA2 carriers on whom more information is available.

Breast Neoplasms↗
PubMed2005

Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population.

We have developed a mutation-scanning approach suitable for whole population screening for unknown mutations. The method, meltMADGE, combines thermal ramp electrophoresis with MADGE to achieve suitable cost efficiency and throughput. The sensitivity was tested in blind trials using 54 amplicons representing the BRCA1 coding region and a panel of 94 unrelated family breast cancer risk consultands previously screened in a clinical diagnostic laboratory. All 10 common polymorphisms, 15/15 previously identified disease-causing mutations, and three previously untested single base changes were identified. Assays of LDLR exons 3 and 8 were validated in 460 familial hypercholesteremics and detected 8/9 known variants. We then applied the exon 3 assay in several DNA banks representing approximately 8000 subjects with known cholesterol values and applied both assays in one DNA bank (n = 3600). In exon 3 we identified one previously reported moderate mutation, P84S (n = 1), also associated with moderate hypercholesteremia in this subject; an unreported silent variant, N76N (n = 1); and known severe hypercholesteremia splice mutation 313+1G-->A (n = 2). Around exon 8 we identified a paucimorphism (n = 35) at the splice site 1061-8T-->C (known to be in complete linkage disequilibrium with T705I) and unreported sequence variants 1186+11G-->A (n = 1) and D335N G-->A (n = 1). The cholesterol value for D335N was on the 96.2 percentile and for T705I, 2/35 carriers were above the 99th percentile. Thus, variants with predicted severe, moderate, and no effect were identified at the population level. In contrast with case collections, CpG mutations predominated. MeltMADGE will enable definition of the full population spectrum of rare, paucimorphic, severe, moderate (forme fruste), and silent mutations and effects.

Breast Neoplasms↗
PubMed2004

The DNMT3B C-->T promoter polymorphism and risk of breast cancer in a British population: a case-control study.

BACKGROUND: Gene promoter methylation is an important regulator of expression and is a key epigenetic factor in tumorigenesis. DNA methylation is mediated by DNA methyltransferases (DNMTs), of which three active forms have been identified: DNMT1, DNM3A and DNMT3B. The C-->T transition polymorphism (C46359T) in the promoter of the DNMT3B gene, which significantly increases transcriptional activity, has been postulated to increase the propensity for promoter-hypermethylation-mediated silencing of tumour suppressor genes. METHODS: To determine the role of this polymorphism in breast cancer, we genotyped 352 cases and 258 controls from a British population. The breast cancer cases were selected on the basis of either an age at onset of less than 40 years, a family history of breast cancer irrespective of age at onset, or bilateral breast cancer diagnosed after 39 years of age irrespective of family history. RESULTS: The C allele was found to be more common in case subjects than in control subjects (cases, 0.59; controls, 0.54) corresponding to a nominally significant increase in breast cancer risk to heterozygotes and CC homozygotes (odds ratio 1.51, 95% confidence interval 1.01-2.25) in the dominant inheritance model. CONCLUSIONS: Our findings contrast with those of a previous study, which showed that individuals carrying at least one T allele have a significantly increased risk of developing lung cancer. This discrepancy might be an artefact resulting from a chance variation, or it might point to differing influences of promoter hypermethylation in these cancer types.

Adult↗
PubMed2002

Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer.

BACKGROUND: A growing body of evidence suggests that variations in the levels of folate may contribute to the development of cancer. A functional polymorphic variant (C-->T substitution at nucleotide 677) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene results in the conversion of an alanine to a valine and may modify the risk of breast and other cancers. METHOD: We have investigated the possible influence of this MTHFR variant on breast cancer risk in a case-control study of 233 healthy women and 335 women who had breast cancer that occurred under the age of 40 years, bilateral breast cancer or a family history of breast cancer. RESULTS: A significant excess of the valine genotypes was observed among the cases (odds ratio 1.43, 95% confidence interval 1.02-2.00). The effect was more pronounced among the cases with a breast cancer diagnosis under the age of 40 years, with an odds ratio of 1.66 (95% confidence interval 1.12-2.41). A nonsignificant excess of the valine genotypes was observed among the cases with a family history of breast cancer or bilateral breast cancer. CONCLUSIONS: The low activity C677T (valine) genotype of MTHFR may increase the risk of early onset breast cancer.

Adult↗
PubMed2002

Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.

The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.

Australia↗