Dataset Information

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

ABSTRACT: HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106?kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism.

SUBMITTER: Ferrari A

PROVIDER: S-EPMC4947184 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

Ferrari Anthony A Vincent-Salomon Anne A Pivot Xavier X Sertier Anne-Sophie AS Thomas Emilie E Tonon Laurie L Boyault Sandrine S Mulugeta Eskeatnaf E Treilleux Isabelle I MacGrogan Gaëtan G Arnould Laurent L Kielbassa Janice J Le Texier Vincent V Blanché Hélène H Deleuze Jean-François JF Jacquemier Jocelyne J Mathieu Marie-Christine MC Penault-Llorca Frédérique F Bibeau Frédéric F Mariani Odette O Mannina Cécile C Pierga Jean-Yves JY Trédan Olivier O Bachelot Thomas T Bonnefoi Hervé H Romieu Gilles G Fumoleau Pierre P Delaloge Suzette S Rios Maria M Ferrero Jean-Marc JM Tarpin Carole C Bouteille Catherine C Calvo Fabien F Gut Ivo Glynne IG Gut Marta M Martin Sancha S Nik-Zainal Serena S Stratton Michael R MR Pauporté Iris I Saintigny Pierre P Birnbaum Daniel D Viari Alain A Thomas Gilles G

Nature communications 20160713

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positiv ...[more]

PMID: 27406316

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Project description:Objective:The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2-) gastric cancer patients. Patients and methods:Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2- samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses. Results:The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2- samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P=0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P=0.002) in HER2+ samples were higher than those in HER2- samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2- samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2- samples. Conclusion:Differences in genomic landscape between HER2+ and HER2- gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2- gastric cancer.

Project description:Background and objectiveBreast cancer (BC) is currently the most frequently diagnosed cancer and the primary cause of cancer-related death among women worldwide. Human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for 14.5-15% of all BCs, with a relatively poor prognosis. Neoadjuvant therapy (NAT) has become a preferred treatment option for HER2+ BCs. With the continuous emergence of various clinical trials and new treatment concepts in BC, the NAT model has changed from chemotherapy alone to the neoadjuvant combination of anti-HER2-targeted therapy with chemotherapy, neoadjuvant endocrine therapy, and so on. Therefore, an up-to-date review is needed to inform the selection of NAT strategies for HER2+ BCs.MethodsThis review was administrated with literature from the PubMed database. Manuscripts were searched using the following keywords: "neoadjuvant" or "preoperative", "breast cancer" or "breast neoplasm", "HER2+" or "HER2-positive", titles and abstracts were screened and evaluated independently by two authors. Information relating to the efficacy and safety profile of NAT for patients with HER2+ BCs were included and analyzed qualitatively. Only English-language articles were included.Key content and findingsThis review discusses the neoadjuvant situation for the surgical management of HER2-positive BCs around the world. In this paper, we describe the efficacy assessment of NAT, analyze clinical effect and toxicity of chemotherapy, and targeted therapy, including monoclonal antibody, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), and other neoadjuvant treatments in HER2+ BC. The data shows while overall survival is the standard endpoint for efficacy, pathological complete response have been implemented more and more frequently in clinical trials for its convenience. Dual-targeted therapy plus chemotherapy exhibited favorable efficacy in most cases, meanwhile other treatment strategies such as combinations without chemotherapy or including CDK4/6 agents may be applicable in specific situation.ConclusionsAs an important part of BC treatment, NAT is lingering in the stage of continuous development, especially for patients with HER2-positive BC. The challenges we are facing today in this field are dose de-escalation without reducing efficacy and choose suitable combination of agents in clinical practice. Moreover, new biomarkers are warrant for individualize treatment.

Dataset Information

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

Publications

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

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