Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)‐positive breast cancers. However, their efficacy is ...limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti‐estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen‐sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα‐positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression.
Synopsis
The analyses of PRMT5 expression in two large cohorts of luminal breast cancer samples and functional studies revealed a key role of PRMT5 expression in the nucleus of tumor cells in premenopausal women treated with tamoxifen.
Nuclear PRMT5 associates with a strong response to tamoxifen treatment in patients and breast PDXs.
Nuclear PRMT5 is an independent prognosis marker for luminal tumors.
Tamoxifen treatment triggers PRMT5 nuclear translocation in the sensitive tumors but not in the resistant one.
Tamoxifen triggers PRMT5‐induced ERα methylation (SDMA), a key event to recruit transcriptional corepressors.
The analyses of PRMT5 expression in two large cohorts of luminal breast cancer samples and functional studies revealed a key role of PRMT5 expression in the nucleus of tumor cells in premenopausal women treated with tamoxifen.
Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or ...the exon-intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols.
We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach.
Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5' splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3' or mutated 5' splice sites.
This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention.
Some studies suggested a decreased ovarian reserve among BRCA1/2 pathogenic variant carriers, with conflicting results.
We conducted a retrospective single-center observational study of ovarian ...reserve and spontaneous fertility comparing BRCA1/2 pathogenic variant carriers to controls (women who attended consultations to discuss fertility preservation before gonadotoxic treatment). Measures of associations between plasma AMH concentration, AFC and BRCA1/2 status were modelled by nonlinear generalized additive regression models and logistic regressions adjusted for age at plasma storage, oral contraceptive use, body mass index, cigarette smoking, and the AMH assay technique.
The whole population comprised 119 BRCA1/2 pathogenic variant carriers and 92 controls. A total of 110 women (42 carriers, among whom 30 were cancer-free, and 68 controls) underwent an ovarian reserve evaluation. Spontaneous fertility analysis included all women who previously attempted to become pregnant (134 women).
We observed a tendency towards a premature decrease in ovarian reserve in BRCA1/2 pathogenic variant carriers, but no difference in mean AMH or AFC levels was found between BRCA1/2 pathogenic variant carriers and controls. An analysis of the extreme levels of AMH (≤5 pmol/l) and AFC (≤7 follicles) by logistic regression suggested a higher risk of low ovarian reserve among BRCA1/2 pathogenic variant carriers (adjusted odds ratio (OR) = 3.57, 95% CI = 1.00–12.8, p = 0.05; and adjusted OR = 4.99, 95% CI = 1.10–22.62, p = 0.04, respectively).
Attention should be paid to BRCA1/2 pathogenic variant carriers’ ovarian reserve, considering this potential risk of premature alteration.
•A tendency towards a premature decrease in the ovarian reserve in BRCA1/2 pathogenic variant carriers was found.•BRCA1/2 pathogenic variant carriers presented a higher risk of a low ovarian reserve.•Information and education regarding reproduction is mandatory among BRCA1/2 pathogenic variant carriers.
After a diagnosis of colorectal cancer (CRC), approximately 50% of patients will present distant metastasis. Although significant progress has been made in treatments, most of them will die from the ...disease. We investigated the predictive and prognostic potential of APC11, the catalytic subunit of APC/C, which has never been examined in the context of CRC. The expression of APC11 was assessed in CRC cell lines, in tissue microarrays (TMAs) and in public datasets. Overexpression of APC11 mRNA was associated with chromosomal instability, lymphovascular invasion and residual tumor. Regression models accounting for the effects of well-known protein markers highlighted association of APC11 protein expression with residual tumor (odds ratio: OR = 6.51; 95% confidence intervals: CI = 1.54-27.59; P = 0.012) and metastasis at diagnosis (OR = 3.87; 95% CI = 1.20-2.45; P = 0.024). Overexpression of APC11 protein was also associated with worse distant relapse-free survival (hazard ratio: HR = 2.60; 95% CI = 1.26-5.37; P = 0.01) and worse overall survival (HR = 2.69; 95% CI = 1.31-5.51; P = 0.007). APC11 overexpression in primary CRC thus represents a potentially novel theranostic marker of metastatic CRC.
In France, it is recommended that girls and women aged 14-23 are vaccinated against the human papillomavirus (HPV). However, French women's knowledge of and attitude towards the vaccine has been ...little studied.
Thirty-nine general practitioners, representative of those working in the large Rhône-Alpes region, offered a self-administered questionnaire on cervical cancer (CC) prevention to all 18-65 year-old women who came for consultation during June and July 2008. In addition, semi-structured interviews were undertaken with a sample of those who had daughters aged 14-18.
Of the 1,478 women who completed the questionnaire, only 16.9% mentioned HPV as the cause of CC, even though 76.2% knew of the vaccine. 210 women had daughters aged 14-18, and 32 were interviewed. Compared with the wider group, more of these women were aware of the HPV vaccine (91.4%). 44.8% knew the target population and 17.1% the recommended ages for vaccination. 54.3% favoured HPV vaccination; 37.2% were undecided and only 0.9% were opposed. The main barrier to acceptance was the recency of the vaccine's introduction and concern about possible side effects (54.9%); 14.1% preferred to rely on their GP's decision. Factors associated with acceptance of the HPV vaccine were having previously vaccinated a child against pneumococcus (OR=3.28 1.32-8.11) and knowing the target population for HPV vaccination (OR=2.12 1.15-3.90). Knowing the recommended frequency of Papanicolaou smear testing (Pap test) screening was associated with lower acceptance (OR=0.32 0.13-0.82).
Few mothers are opposed to HPV vaccination. Factors associated with acceptability were knowledge about the vaccine, acceptance of other vaccines and, unexpectedly, lack of knowledge about the recommended frequency of Pap testing. On multivariate analysis, compliance with recommendations for Pap test screening and socioeconomic factors had no effect on views about HPV vaccination. Given that concern about possible side effects is the major barrier to wider acceptance of the HPV vaccine in France, GPs have a key role in providing information.
The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis ...and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including
(n = 203, 38%),
(n = 198, 37%),
(n = 46, 9%),
(n = 36, 7%),
(n = 16, 3%), and
(n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.
The disclosure of genetic information is an important issue in cancer prevention. This study based on a French national cohort of BRCA1/2 mutation carriers (GENEPSO-PS cohort, N=233) aimed to assess ...the prevalence of parental disclosure of genetic information to children 10 years after genetic testing, with a focus on gender differences. Most participants (n = 193, 131 women) reported having children. A total of 72.0% of offspring had received genetic information (88.8% for adult offspring, p < .001), with no differences according to the gender of the mutation-carrying parent. While female carriers disclosed genetic information more often than male carriers (54.1% versus 38.3%, p = .029), they did so irrespective of the gender of their offspring. Moreover, female carriers who had developed incident cancer after genetic testing disclosed genetic information more frequently than unaffected female carriers (70.7% versus 48.5%, p = .005). A multivariate analysis confirmed the effects of both gender and cancer on disclosure to offspring. The same results were obtained when the analysis was restricted to adult offspring. This study reveals high rates of disclosure of positive BRCA1/2 mutation status to children 10 years after genetic testing, irrespective of the gender of the carrier/offspring. However, female carriers disclosed genetic information more frequently than male carriers.
Few clinical prognostic factors have been identified for patients with metastatic renal cell carcinoma (MRCC), and no biomarker is known in this disease. Several endogenous cytokines have ...demonstrated interesting and significant correlations with survival in these patients. Our objective was to analyze the prognostic value of circulating vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and interleukin-6 (IL-6).
Serum levels of IL-6, IL-10, and VEGF were measured in patients with MRCC. Their prognostic value for response to treatment and progression-free and overall survival was evaluated. Pretreatment samples were obtained from 138 patients of a large randomized multicentric trial. Endogenous cytokine levels were determined using immunoassays. Univariate and multivariate analyses were performed to evaluate the prognostic value of each factor further controlled by an internal validation test. Threshold values for serum IL-6 and VEGF were determined using the quartile method.
Serum IL-6 was detectable in 70% of the patients. IL-10 and VEGF were elevated in 8% and 71% of the patients, respectively. None of these circulating factors was correlated with response to treatment. IL-10 was not significantly correlated with progression-free or overall survival. Despite significant correlation with survival, VEGF was not an independent prognostic factor in the multivariate analysis. Finally, IL-6 was significantly correlated with progression-free survival and overall survival, and has prognostic value for overall survival.
Circulating IL-6 level appears to be an important independent prognostic factor in patients with MRCC; if confirmed in further studies, it could be considered for treatment decisions in these patients.
We aimed to study the relationships between educational level, women's knowledge about cervical cancer (CC), and acceptance of HPV vaccination for their daughters.
We analysed data from a ...quantitative (self-administrated questionnaire) and qualitative (semi-structured interviews) cross-sectional study performed in 2008 among 1,229 French 18-65-year-old women recruited by general practitioners. Women were categorized into three educational level groups: low (LEL: 43.9%), medium (MEL: 33.4%) and high (HEL: 22.6%).
Knowledge about CC and its prevention was lower among LEL women. In the 180 mothers of 14-18-year-old daughters (99 LEL, 54 MEL, 45 HEL), acceptance of HPV vaccine was higher in LEL (60.4%) and MEL (68.6%) than in HEL mothers (46.8%). Among LEL mothers, those who were favourable to HPV vaccination were more likely to be young (OR = 8.44 2.10-34.00), to be vaccinated against hepatitis B (OR = 4.59 1.14-18.52), to have vaccinated their children against pneumococcus (OR = 3.52 0.99-12.48) and to present a history of abnormal Pap smear (OR = 6.71 0.70-64.01).
Although LEL women had poorer knowledge about CC and its prevention, they were more likely to accept HPV vaccination than HEL mothers.
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