Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

Ciriello, Giovanni; Gatza, Michael L.; Beck, Andrew H.; Wilkerson, Matthew D.; Rhie, Suhn Kyong; Pastore, Alessandro; Zhang, Hailei; McLellan, Michael D.; Yau, Christina; Kandoth, Cyriac; Bowlby, Reanne; Shen, Hui; Hayat, Sikander; Fieldhouse, Robert J.; Lester, Susan C.; Tse, Gary M.; Factor, Rachel E.; Collins, Laura C.; Allison, Kimberly H.; Chen, Yunn Yi; Jensen, Kristin C.; Johnson, Nicole B.; Oesterreich, Steffi; Mills, Gordon B.; Cherniack, Andrew D.; Robertson, Gordon; Benz, Christopher C.; Sander, Chris; Laird, Peter W.; Hoadley, Katherine A.; King, Tari A.; Akbani, Rehan; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Barr, Thomas; Benz, Stephen; Berríos, Mario; Beroukhim, Rameen; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Bowen, Jay; Brooks, Denise; Chin, Lynda; Cho, Juok; Chudamani, Sudha; Davidsen, Tanja M.; Demchok, John A.; Dennison, Jennifer B.; Li, Ding; Felau, Ina; Ferguson, Martin L.; Frazer, Scott; Gabriel, Stacey; Gao, Jian; Gastier‐Foster, Julie M.; Gehlenborg, Nils; Gerken, Mark; Getz, Gad; Gibson, William J.; Hayes, D. Neil; Heiman, David I.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Hu, Hai; Huang, Mei; Hutter, Carolyn M.; Hwang, E. Shelley; Jefferys, Stuart R.; Jones, Steven J.M.; Zhang, Ju; Kim, Jaegil; Lai, Phillip H.; Lawrence, Michael S.; Leraas, Kristen; Lichtenberg, Tara M.; Lin, Pei; Ling, Shiyun; Liu, Jia; Liu, Wenbin; Lolla, Laxmi; Lu, Yiling; Ma, Yussanne; Maglinte, Dennis T.; Mardis, Elaine R.; Marks, Jeffrey R.; Marra, Marco A.; McAllister, Cynthia; Meng, Shaowu; Meyerson, Matthew; Moore, Richard A.; Mose, Lisle E.; Mungall, Andrew J.; Murray, Bradley A.; Naresh, Rashi; Noble, Michael S.; Olopade, Olufunmilayo; Parker, Joel S.; Pihl, Todd; Saksena, Gordon; Schumacher, Steven E.; Shaw, Kenna; Ramirez, Nilsa C.; Rathmell, W. Kimryn; Roach, Jeffrey; Robertson, A. Gordon; Schein, Jacqueline E.; Schultz, Nikolaus; Sheth, Margi; Shi, Yan; Shih, Juliann; Shelley, Carl Simon; Shriver, Craig D.; Simons, Janae V.; Sofia, Heidi J.; Soloway, Matthew G.; Sougnez, Carrie; Sun, Charlie; Tarnuzzer, Roy; Tiezzi, Daniel Guimarães; Berg, David J. Van Den; Voet, Doug; Wan, Yunhu; Wang, Zhining; Weinstein, John N.; Weisenberger, Daniel J.; Wilson, Richard K.; Wise, Lisa; Wiznerowicz, Maciej; Wu, Junyuan; Wu, Ye; Yang, Liming; Zack, Travis I.; Zenklusen, Jean C.; Zhang, Jiashan; Zmuda, Erik; Perou, Charles M.

doi:10.1016/j.cell.2015.09.033

Cited by 1,589 publications

(1,822 citation statements)

References 67 publications

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“…The 1,100 BRCA cases with RNAseq data were filtered to exclude male and gender “unknown” samples (n = 13), metastatic tissue samples (n = 7) and one errant skin cancer sample yielding 1,079 female primary breast tumor samples for downstream expression analysis. PAM50 intrinsic molecular subtype assignments and PAM50 proliferation scores were computed as previously described, 48,49 and are available in eWorksheet 1 in Supplement 2. The subtypes segregate as follows: Basal-like (n = 189), HER2E (n = 82), LumA (n = 559), LumB (n = 209) and Normal-like (n = 40).…”

Section: Methodsmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Methodsmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…To address this question, we analyzed the publicly available TCGA breast cancer data set using online interface, cBioPortal query algorithm and also included the genes characterized in Figures 1 and 2 (CCND1, PLK1, TPX2, PTEN, ESR1 and TP53), which represent the biological hallmarks of human breast cancer. First, review of TCGA data set revealed that Aurora-A copy gain/elevated expression was present in about 53% of the 971 breast cancers analyzed (29). Second, altered copy number/expression profiles observed in BLG-Aurora-A mouse mammary tumors (GLP1R, CCND1, PLK1, TPX2, ERCC5, PTEN, TCF7L2, ESR1 and TP53) were found to significantly co-occur with Aurora-A copy gain/overexpression in human breast cancer TCGA data set (Table 1).…”

Section: Co-occurrence Of Copy Number-altered Genes With Aurora-a Copmentioning

confidence: 99%

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Treekitkarnmongkol

Katayama

Kai

et al. 2016

CARCIN

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Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

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“…2B and Dataset S1, Table S4), indicating that our screen is selecting for genes that are relevant to many types of cancer. Finally, we used the TCGA breast cancer database (37,38) to identify genes mutated in human breast cancer (i.e., missense, nonsense, sense, and in-frame mutations). Among the 1,375 mutated genes listed in TCGA, 70 are SB-identified CCGs (P = 9.21E-12, two-sided Fisher's exact test; Fig.…”

Section: Sb Mutagenesis Promotes the Development Of Multiple Breast Cmentioning

confidence: 99%

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.Sleeping Beauty | breast cancer | TRPS1 | metastasis | tumor suppressors B reast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and basal-like (1-5). Basal-like or triplenegative breast cancer (TNBC) constitutes 10-20% of all breast cancers and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1, 3-5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6-8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9, 10). Mutations in PTEN drive epithelial-mesenchymal transition (EMT) and promote metastasis in TNBC (11-13). Similarly, in mice, heterozygous deletion of Pten induces mammary tumors with basal-like characteristics (14)(15)(16)(17).Despite all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18-26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes. Transposon insertions in tumors thus serve as molecular tags for the high-throughput cloning and identification of cancer genes. In addition, because transposon insertions are PCR-amplified before they are sequenced, insertional mutations in cancer genes that are present in only a small fraction of tumor cells can be identified. Transposon mutagenesis can thus identify genes that are functioning at th...

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Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

Cited by 1,589 publications

References 67 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

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