Detoxification: A Novel Function of BRCA1 in Tumor Suppression?

Our studies found that BRCA1 levels negatively correlate with DNA adducts induced by Benzo(a)pyrene (BaP). Pulse-chase experiments showed that the increase in BaP-induced DNA adducts in BRCA1 knockdown cells may not be associated with BRCA1’s function in nucleotide excision repair activity; rather, it may be associated with its function in modulating transcriptional regulation. BRCA1 knockdown in MCF-10A cells significantly attenuated the induction of CYP1A1 following BaP treatment indicating that the increase in BaP-induced adducts in BRCA1 knockdown cells is not CYP1A1 dependent. However, our study shows that BRCA1 defective cells may still be able to biotransform BaP by regulating other CYP enzymes, including CYP1B1. Knockdown of BRCA1 also severely affected the expression levels of two types of uridine diphosphate glucorunyltransferase (UGT1A1 and UGT1A9) and NRF2. Both UGTs are known as BaP-specific detoxification enzymes, and NRF2 is a master regulator of antioxidant and detoxification genes. Thus, we concluded that the increased amount of BaP-induced DNA adducts in BRCA1 knockdown cells is strongly associated with its loss of functional detoxification. Chromatin immunoprecipitation assay revealed that BRCA1 is recruited to the promoter/enhancer sequences of UGT1A1, UGT1A9, and NRF2. Regulation of UGT1A1 and UGT1A9 expression showed that the induction of DNA adducts by BaP is directly affected by their expression levels. Finally, overexpression of UGTs, NRF2, or ARNT significantly decreased the amount of BaP-induced adducts in BRCA1-deficient cells. Overall, our results suggest that BRCA1 protects cells by reducing the amount of BaP-induced DNA adducts possibly via transcriptional activation of detoxification gene expression

On the avoidability of breast cancer in industrialized societies: older mean age at first birth as an indicator of excess breast cancer risk

Background Breast cancer incidence continuous to increase. We examined at population level the association between the relative excess risk of breast cancer and previous age of mother at first birth. Method Incidence of breast cancer in 34 industrialized countries was obtained from the GLOBOCAN 2002 and SEER databases. Data on age of mother at first birth was collected through national statistics offices. National relative excess risk (RER) was calculated by subtracting the lowest age-specific incidence rate from the rate in each population, and dividing the difference by the latter. Results The national RER in 2002 correlated closely with a higher average age at first birth in 1972, 1982, 1992 and also 2002, Pearson correlation [r] being 0.83, 0.79, 0.72 and 0.61, respectively; P < 0.0001. RER of breast cancer in 2002 for those aged 15–44 years correlated closely with the mean age at first birth in 1982 and 1992 (r: 0.81 and 0.75; P < 0.0001), whereas RER for those aged 45–54 years correlated strongly with age at first birth in 1972 and 1982 (r: 0.81 and 0.76; P < 0.0001), and for those aged 55–64 years with age at first birth in 1972 (r: 0.77; P < 0.0001). Conclusions The rising age at first childbirth of mothers has been followed by marked increases in breast cancer incidence. Later age at first birth seems to characterize secular diffusion of ‘modern’ lifestyles with a potentially large impact on increased breast cancer risk, and hence should be accompanied by greater opportunities for prevention through modifiable risk factors

Retrospective analysis of molecular scores for the prediction of distant recurrence according to baseline risk factors

This work was funded by grants from Cancer Research UK (programme Grant C569-A16891), the Royal Marsden NIHR Biomedical Research Centre, and AstraZenec

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases

Guidelines for Disclosing Genetic Information to Family Members: from Development to Use

[À l'origine dans / Was originally part of : CRDP - Droit, biotechnologie et rapport au milieu

Evaluation of association methods for analysing modifiers of disease risk in carriers of high-risk mutations

There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL—CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias—RB: −25% to −17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: −2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Family history of breast cancer and its association with disease severity and mortality

A family history (FH) of breast cancer (BC) is known to increase an individual's risk of disease onset. However, its role in disease severity and mortality is less clear. We aimed to ascertain associations between FH of BC, severity and BC-specific mortality in a hospital-based cohort of 5354 women with prospective information on FH. We included women diagnosed at Guy's and St Thomas' NHS Foundation Trust between 1975 and 2012 (n = 5354). BC severity was defined and categorized as good, moderate, and poor prognosis. Data on BC-specific mortality was obtained from the National Cancer Registry and medical records. Associations between FH and disease severity or BC-specific mortality were evaluated using proportional odds models and Cox proportional hazard regression models, respectively. Available data allowed adjustment for potential confounders (e.g., treatment, socioeconomic status, and ethnicity). FH of any degree was not associated with disease severity at time of diagnosis (adjusted proportional OR: 1.00 [95% CI: 0.85 to 1.17]), which remained true also after stratification by period of diagnosis. FH of BC was not associated with BC-mortality HR: 0.99 (95% CI: 0.93 to 1.05). We did not find evidence to support an association between FH of BC and severity and BC-specific mortality. Our results indicate that clinical management should not differ between women with and without FH, when the underlying mutation is unknown