Marc-Henri Stern

Bio: Marc-Henri Stern is an academic researcher from Curie Institute. The author has contributed to research in topics: Breast cancer & Medicine. The author has an hindex of 49, co-authored 168 publications receiving 9402 citations. Previous affiliations of Marc-Henri Stern include Necker-Enfants Malades Hospital & French Institute of Health and Medical Research.

Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation

Abstract: BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.

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

Abstract: 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.

U1 snRNP regulates cancer cell migration and invasion in vitro

Abstract: 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.

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Abstract: 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.)

Triple-negative breast cancer.

Abstract: 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.