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

Ferrari, Anthony; Vincent‐Salomon, Anne; Pivot, Xavier; Sertier, Anne-Sophie; Thomas, Emilie; Tonon, Laurie; Boyault, Sandrine; Mulugeta, Eskeatnaf; Treilleux, Isabelle; MacGrogan, Gaëtan; Arnould́, Laurent; Kielbassa, Janice; Texier, Vincent Le; Blanché, Hélène; Deleuze, Jean‐François; Jacquemier, Jocelyne; Mathieu, Marie‐Christine; Penault‐Llorca, Frédérique; Bibeau, Frédéric; Mariani, Odette; Mannina, Cécile; Pierga, Jean‐Yves; Trédan, Olivier; Bachelot, Thomas; Bonnefoi, Hervé; Romieu, Gilles; Fumoleau, P.; Delaloge, Suzette; Rios, María; Ferrero, Jean-­Marc; Tarpin, Carole; Bouteille, C.; Calvo, Fabien; Gut, Marta; Gut, Marta; Martin, Sancha; Nik-Zainal, Serena; Stratton, Michael R.; Pauporté, Iris; Saintigny, Pierre; Birnbaum, Daniel; Viari, Alain; Thomas, Gilles

doi:10.1038/ncomms12222

Cited by 125 publications

(124 citation statements)

References 68 publications

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“…The distribution of the types of alterations was different from that of IBC ( P = 1.24E‐17, Fisher's exact test) with a lesser percent of mutations (70% vs 78%, corresponding to 62% vs 66% for SNVs, and 8% vs 12% for indels). The gene alterations identified in non‐IBC confirmed the literature data (Banerji et al , ; Ellis et al , ; Ferrari et al , ; Nik‐Zainal et al , ; Nik‐Zainal et al , ; Nik‐Zainal et al , ; Shah et al , ; Stephens et al , ; Cancer Genome Atlas, ), that is, the most frequently altered genes including PIK3CA (39%), TP53 (34%), HER2 (13%), GATA3 (13%), KMT2C (11%), CDH1 (10%), and MAP3K1 (10%). The mean TMB for all variants was higher in IBC (six mutations/Mb; CI95, 4–8) than in non‐IBC (2; CI95, 2–2; Student's t ‐test, P = 6.29E‐05; Fig.…”

Section: Resultssupporting

confidence: 80%

“…During the last decade, next‐generation sequencing (NGS) led to identification of driver alterations in non‐IBC (Banerji et al , ; Ellis et al , ; Ferrari et al , ; Nik‐Zainal et al , ; Nik‐Zainal et al , ; Nik‐Zainal et al , ; Shah et al , ; Stephens et al , ; The Cancer Genome Atlas, ). Precision medicine trials have shown the potential of DNA‐based genomics screening to identify clinically actionable genetic alterations (AGAs) for guiding treatment (Andre et al , ; Le Tourneau et al , ).…”

Section: Introductionmentioning

confidence: 99%

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NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

et al. 2020

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Inflammatory breast cancer (IBC) is the most pro‐metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non‐IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next‐generation sequencing (tNGS) and array‐comparative genomic hybridization (aCGH) to 57 IBC and 50 non‐IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non‐IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor‐positive (HR+)/HER2−, HER2+, and triple‐negative] were 68%, 15%, and 17% in non‐IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non‐IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non‐IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non‐IBC. Ninety‐seven percent of IBCs displayed at least one AGA. This percentage was higher than in non‐IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non‐IBC. The genomic landscape of IBC is different from that of non‐IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

et al. 2020

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“…By comparison, a previous study investigating recurrent ESR1‐CCDC170 fusions suggested a degree of enrichment of such fusions in HER‐positive patients (luminal A .9%, luminal B 2.9% and HER2 3.1%) . We also detected an intra‐chromosomal ERBB2‐ORMDL3 frameshift fusion within 230 kbp of 17q12, a distance longer than the reported 106‐kbp ERBB2 amplicon region …”

Section: Discussionsupporting

confidence: 56%

Integrative molecular profiling identifies a novel cluster of estrogen receptor‐positive breast cancer in very young women

et al. 2019

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Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor ( ER )‐positive breast cancer by analyzing mutations and copy number variants ( CNV ), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer ( KYBR ) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER + breast cancer patients in The Cancer Genome Atlas ( TCGA ) dataset. TP 53 , PIK 3 CA and GATA 3 were highly recurrent somatic mutation genes. APOBEC ‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF 1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC 3A/B deletions, respectively. Group B was characterized by 11q13 ( CCND 1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 ( ERBB 2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition ( EMT ) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.

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“…Recent massive parallel sequencing studies have revealed that HER2 can drive breast cancer growth not only by amplification in HER2+ breast cancer but also through HER2-activating mutations preferentially in breast cancers lacking HER2 overexpression and/or gene amplification (20, 21). HER2 mutations occur in about ~3% of breast cancer patients, among which the HER2 L755S mutation is the most common (results based on the Cancer Genome Atlas Study (TCGA; cBioPortal) (22, 23).…”

Section: Introductionmentioning

confidence: 99%

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Angelis

Burke

et al. 2017

Clinical Cancer Research

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Purpose Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. Experimental Design Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the L-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared to parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition. Results Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired L resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2 irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo. Conclusion HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.

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

Cited by 125 publications

References 68 publications

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

Integrative molecular profiling identifies a novel cluster of estrogen receptor‐positive breast cancer in very young women

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

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