12 results found
Cereser B, Tabassum N, Belluz LDB, et al., 2020, Mutational landscapes of normal breast during age and pregnancy determine cancer risk, Biorxiv
<h4>ABSTRACT</h4> The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood 1–10 . Similarly, the mutational landscape of both epithelial and stromal components of the mammary gland has not been investigated. Both are relevant for breast cancer (BC), as the interplay between age, pregnancy, and cancer risk has not been fully characterized 11 . We describe whole genome sequencing analysis of epithelial and stromal compartments from the normal breast. We show that, in a similar way to other normal organs, the mutational burden of the mammary nulliparous epithelium significantly increases with age. In a nulliparous status, mutated clones are maintained at a consistently small size throughout the life of the individual; however, at parity, pre-existent clones significantly increase in size with age. Both epithelial and stromal compartments of the healthy breast contain pre-existing known cancer mutations, albeit at low rate, indicative of subsequent positive selection for mutations in tissue-specific driver genes. In line with this, both compartments also present gene enrichment in preferentially mutated cancer pathways. Our results show that mutational landscapes differ between the parous and nulliparous epithelium and suggest an explanation for both differential breast cancer risk and development of pregnancy-associated BC (PABC).
Aflorei ED, Klapholz B, Chen C, et al., 2018, In vivo bioassay to test the pathogenicity of missense human AIP variants, Journal of Medical Genetics, Vol: 55, Pages: 522-529, ISSN: 0022-2593
Background Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up.Objective To develop an in vivo system to test the pathogenicity of human AIP mutations using the fruit fly Drosophila melanogaster.Methods We generated a null mutant of the Drosophila AIP orthologue, CG1847, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants (CG1847exon1_3 ). We tested human missense variants of ‘unknown significance’, with ‘pathogenic’ variants as positive control.Results We found that human AIP can functionally substitute for CG1847, as heterologous overexpression of human AIP rescued male CG1847exon1_3 lethality, while a truncated version of AIP did not restore viability. Flies harbouring patient-specific missense AIP variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue CG1847exon1_3 mutants, while seven variants (p.R16H, p.Q164R, p.E293V, p.A299V, p.R304Q, p.R314W and p.R325Q) showed rescue, supporting a non-pathogenic role for these latter variants corresponding to prevalence and clinical data.Conclusion Our in vivo model represents a valuable tool to characterise putative disease-causing human AIP variants and assist the genetic counselling and management of families carrying AIP variants.
Carter P, Alifrangis CC, Cereser B, et al., 2018, Molecular profiling of advanced breast cancer tumors is beneficial in assisting clinical treatment plans, Oncotarget, Vol: 9, Pages: 17589-17596, ISSN: 1949-2553
We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used.Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival.
Carter P, Alifrangis C, Cereser B, et al., 2018, Correction: Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 15166-15166, ISSN: 1949-2553
Corrections for article DOI: 10.18632/oncotarget.24258
Carter P, Alifrangis C, Cereser B, et al., 2018, Correction: Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 15164-15164, ISSN: 1949-2553
Correction to article DOI: https://dx.doi.org/10.18632/oncotarget.23675
Carter P, Alifrangis C, Chandrasinghe P, et al., 2018, Correction: The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 15165-15165, ISSN: 1949-2553
Corrections for article DOI: https://dx.doi.org/10.18632/oncotarget.24257.].
Alifrangis C, Carter P, Cereser B, et al., 2018, Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments., Oncotarget, Vol: 9, Pages: 12805-12811, ISSN: 1949-2553
In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not (P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group (P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival.
Carter P, Alifrangis CC, Chandrasinghe P, et al., 2018, The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 11371-11376, ISSN: 1949-2553
We evaluated the benefit of tailoring treatments for a colorectal adenocarcinoma cancer cohort according to tumor molecular profiles, by analyzing data collected on patient responses to treatments that were guided by a tumor profiling technology from Caris Life Sciences. DNA sequencing and immunohistochemistry were the main tests that predictions were based upon, but also fragment analysis, and in situ hybridization. The status of the IHC biomarker for the thymidylate synthase receptor was a good indicator for future survival. Data collected for the clinical treatments of 95 colorectal adenocarcinoma patients was retrospectively divided into two groups: the first group was given drugs that always matched recommended treatments as suggested by the tumor molecular profiling service; the second group received at least one drug after profiling that was predicted to lack benefit. In the matched treatment group, 19% of patients were deceased at the end of monitoring compared to 49% in the unmatched group, indicating a benefit in mortality by tumor molecular profiling colorectal adenocarcinoma patients.
Carter P, Alifrangis CC, Cereser B, et al., 2018, Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 9456-9467, ISSN: 1949-2553
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers.Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations.The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).
Carter P, Alifrangis C, Cereser B, et al., 2017, Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 6007-6014, ISSN: 1949-2553
Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients).In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.
Orme MH, Liccardi G, Moderau N, et al., 2016, The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles, Nature Communications, Vol: 7, ISSN: 2041-1723
Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events.
Bader R, Sarraf-Zadeh L, Peters M, et al., 2013, The IGFBP7 homolog Imp-L2 promotes insulin signaling in distinct neurons of the Drosophila brain, JOURNAL OF CELL SCIENCE, Vol: 126, Pages: 2571-2576, ISSN: 0021-9533
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.