Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

/pdf/identification-of-human-triple-negative-breast-cancer-3rvotimac1.pdf

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Stimulated cells and cancer cells have widespread shortening of mRNA 3'-untranslated regions (3'UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons. U1 snRNP (U1), vertebrates' most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread premature transcription termination and mRNA shortening. Here we show that low U1 AMO doses increase cancer cells' migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect. In addition to 3'UTR length, numerous transcriptome changes that could contribute to this phenotype are observed, including alternative splicing, and mRNA expression levels of proto-oncogenes and tumor suppressors. These findings reveal an unexpected role for U1 homeostasis (available U1 relative to transcription) in oncogenic and activated cell states, and suggest U1 as a potential target for their modulation.

/pdf/u1-snrnp-regulates-cancer-cell-migration-and-invasion-in-4wdiaemkkl.pdf

U1 snRNP regulates cancer cell migration and invasion in vitro

https://spiral.imperial.ac.uk/bitstream/10044/1/71213/5/1-s2.0-S1074761318301213-main.pdf

The Immune Landscape of Cancer

Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

/pdf/age-related-clonal-hematopoiesis-associated-with-adverse-1pxvez9t4c.pdf

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1001389

Triple-negative breast cancer.

The present invention relates to an oligonucleotide that can be used to identify individuals with an increased risk for the development of lymphoid leukemia and/or lymphoma and to a test kit containing the oligonucleotides. The invention also relates to method of identifying individuals and/or populations of individuals at an increased risk for the development of lymphoid leukemia and/or lymphoma. The invention further relates to a method for identification of individuals for the autosomal recessive disease ataxia-telangiectasia and related syndromes. The invention further relates to a method of identifying carcinogenic compounds.

A screening test that identifies individuals at increased risk for the development of lymphoid leukemia and lymphoma

The invention relates to the domain of anemia, iron overload and myeloid malignancy. The inventors identify a variant transcript of ERFE specific of SF3B1 MUT MDS that contributes to increased concentration of ERFE protein leading to hepcidin suppression and iron accumulation in patients. This transcript contains an in-frame added intronic sequence of 12 nucleotides not inducing a stop codon that may be translated into a variant protein with an additional 4 amino acids. By using deep mass spectrometry, they identified a peptide corresponding to the added polypeptide VPQF (SEQ ID NO: 5) demonstrating the active production of a variant protein by bone marrow erythroblasts of patients with a SF3B1- mutated MDS. This variant can be used as a pertinent biomarker of clonal erythropoiesis for monitoring treatments of anemia in SF3B1 MUT patients. Thus, the invention relates to a variant of the transcript of ERFE and its use in diagnosing and monitoring of anemia and iron overload in patient with a myeloid malignancy with at least one mutation in the SF3B1 gene.

Variants of erythroferrone and their use


 Background: The TOP2A and ERBB2 genes are co-amplified in about 40% of HER2 positive (HER2+) breast cancers. Oral etoposide (VP16), an inhibitor of topoisomerase-II (encoded by TOP2A), has demonstrated clinical activity in metastatic breast cancer (MBC). However, the clinical benefit of oral VP16 combined with trastuzumab (VP16-T) in HER2+ MBC has not been evaluated.Methods: Patients treated at Institut Curie Hospitals with VP16-T for HER2+ MBC were retrieved by an in-silico search. Trained medical oncologists retrospectively assessed progression-free survival (PFS), overall survival (OS), response rate, prolonged PFS (defined as a duration of at least 6 months), 6 months clinical benefit rate and toxicity. Co-amplification of ERBB2 and TOP2A was assessed by shallow whole genome sequencing on tumor tissue whenever available.Results: Forty-three patients received VP16-T after a median number of six prior treatment lines for HER2+ MBC. Median PFS and OS were 2.9 months (95% CI [2.4-4.7]) and 11.3 months (95% CI [8.3-25.0]), respectively. Three patients had a complete response while 12/40 (30%) had a clinical benefit. Only 3 patients stopped treatment for toxicity. Median PFS in the population with and without TOP2A/ERBB2 co-amplification was respectively 4.7 months (95% CI [2.3-NA]) and 2.9 months (95% CI [1.2-NA]; p=0.36).Conclusion: Our analysis suggests a favorable efficacy and toxicity profile for VP16-T in patients with heavily pretreated HER2+ MBC.

https://www.researchsquare.com/article/rs-1325343/latest.pdf

Oral etoposide and trastuzumab in HER2-positive metastatic breast cancer: a retrospective study at Institut Curie Hospitals.

genes rearrangement between T-cell receptor beta and T-cell receptor gamma Inversion of chromosome 7 in ataxia telangiectasia is generated by a

The bevacizumab(bev)/olaparib(ola) maintenance regimen was approved for women affected with BRCA-mutated (BRCAm) and HRD HGOC, based on a greater progression-free survival (PFS) compared to bevacizumab alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). HRD status in this trial was determined by the centralized MyChoice CDx test by Myriad Genetics (MG test). Belonging to the second part of the ENGOT HRD European initiative we evaluated the analytical and clinical validity of the ShallowHRDv2 test, an assay that analyzes the genome-wide copy number alterations, as compared with the MG test on PAOLA-1/ENGOT-ov25 tumor samples. We performed shallow Whole Genome Sequencing (sWGS) with a mean coverage of ∼1x (XT-HS capture kit; Agilent) on 449 tumor DNAs from the PAOLA-1/ENGOT-OV25 trial. HRD status was determined using the shallowHRDv2 bio-informatics pipeline with a single cut-off at 20 Large scale Genomic Alterations. We further evaluated our test on 109 prospective samples from our routine practice. In the PAOLA-1 cohort, positive agreement for the ShallowHRDv2 vs. MG test status was 95% (196/206), negative agreement was 92% (173/188) and the overall agreement was 94% (369/394). Patients with shallowHRDv2-HRD-positive (including BRCAm) tumors showed a significantly prolonged PFS with bev/ola versus bev/placebo (median PFS: 44.8 vs. 20.3 months, hazard ratio (HR): 0.35 [95% CI, 0.23–0.54]). This benefit was still significant after exclusion of BRCAm tumors (41.7 vs. 18.6 months, HR: 0.47 [95% CI, 0.27–0.84]). Less non-contributive analyses were observed with the ShallowHRDv2 test (15/449; 3%) than with MG test (51/449; 11%). We confirmed the high overall percentage agreement of 91% (86/94) between ShallowHRDv2 and MG tests in the prospective cohort, with less non contributive results for ShallowHRDv2 (5% vs. 12%). The ShallowHRDv2 test is a robust, cost-effective, clinically validated & highly performant test for HRD determination and is a valid alternative to MG to detect HRD in ovarian cancers. 

http://www.esmoopen.com/article/S2059702923000388/pdf

38MO Validation study of the ShallowHRDv2 assay for homologous recombination deficiency (HRD) detection in high-grade ovarian carcinomas (HGOC) in the first-line setting, from the phase III PAOLA-1/ENGOT-ov25 trial

Marc-Henri Stern

Papers

A screening test that identifies individuals at increased risk for the development of lymphoid leukemia and lymphoma

Variants of erythroferrone and their use

Oral etoposide and trastuzumab in HER2-positive metastatic breast cancer: a retrospective study at Institut Curie Hospitals.

genes rearrangement between T-cell receptor beta and T-cell receptor gamma Inversion of chromosome 7 in ataxia telangiectasia is generated by a

38MO Validation study of the ShallowHRDv2 assay for homologous recombination deficiency (HRD) detection in high-grade ovarian carcinomas (HGOC) in the first-line setting, from the phase III PAOLA-1/ENGOT-ov25 trial