Integrative clinical genomics of metastatic cancer

Robinson, Dan R.; Wu, Yi; Lonigro, Robert J.; Vats, Pankaj; Cobain, Erin F.; Everett, Jessica N.; Cao, Xuhong; Rabban, Erica; Kumar‐Sinha, Chandan; Raymond, Victoria M.; Schuetze, Scott M.; Alva, Ajjai; Siddiqui, Javed; Chugh, Rashmi; Worden, Francis P.; Zalupski, Mark M.; Innis, Jeffrey W.; Mody, Rajen; Tomlins, Scott A.; Lucas, David R.; Baker, Laurence H.; Ramnath, Nithya; Schott, Ann F.; Hayes, Daniel F.; Vijai, Joseph; Offit, Kenneth; Stoffel, Elena M.; Roberts, Jonathan; Smith, David C.; Kunju, Lakshmi P.; Talpaz, Moshe; Cieślik, Marcin; Chinnaiyan, Arul M.

doi:10.1038/nature23306

Cited by 749 publications

(698 citation statements)

References 44 publications

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“…4b and 5a). These two mutually exclusive states, which were recently observed in a pan-cancer genomic analysis of metastatic tumors 41 , likely account for the reversibility in chromosome missegregation rates seen in primary tumors and metastases, and provide an explanation for the negative effect of aneuploidy during early tumorigenesis 40,42 . It also leads us to suggest that CIN drives the subset of human metastases characterized by EMT and inflammation 41 .…”

Section: Discussionmentioning

confidence: 67%

Chromosomal instability drives metastasis through a cytosolic DNA response

Bakhoum

Ngo

Laughney

et al. 2018

Nature

1,157

951

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Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

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Section: Discussionmentioning

confidence: 67%

Chromosomal instability drives metastasis through a cytosolic DNA response

Bakhoum

Ngo

Laughney

et al. 2018

Nature

1,157

951

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“…To confirm this observation, we have compiled an extended multi-site metastatic prostate cancer cohort of 360 patients (CRPC360), comprising SU2C (Robinson et al, 2015), MI-OncoSeq (Robinson et al, 2017), and UMich rapid autopsy cases (Grasso et al, 2012) (Table S1), a majority of which have matched whole-exome and transcriptome data (Table S2). The combined data sets were reanalyzed using the MI-Oncoseq workflow (Robinson et al, 2017), producing harmonized call sets of somatic, germline, and structural variants. We also analyzed, using the MI-Oncoseq workflow, sequence data from 498 cases of primary prostate cancer in the TCGA (The Cancer Genome Atlas) dataset.…”

Section: Resultsmentioning

confidence: 91%

“…These studies have discovered common genetic drivers of prostate cancer, such as fusions of ETS genes (Tomlins et al, 2005), amplification of AR , and loss of CDKN2A , PTEN , RB1 , SPOP , and TP53 (Robinson et al, 2015). Integrative genomic studies have further delineated distinct molecular subtypes in primary and metastatic prostate cancer and specific molecular pathways that contribute to prostate cancer onset and progression, including AR , WNT , and PI3K/AKT/MTOR signaling (Barbieri et al, 2012; Beltran et al, 2016; Robinson et al, 2017; The Cancer Genome Atlas Research Network, 2015). …”

Section: Introductionmentioning

confidence: 99%

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

Cieślik

Lonigro

et al. 2018

Cell

Self Cite

472

506

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SUMMARY Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically-localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12-mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12-mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.

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“…Additionally, we cannot exclude the possibility that tumors from different sites may represent variations in molecular subtype or different stages of the disease. Ideally matched samples would better resolve these questions; however, matched samples collected from multiple centers worldwide from a cohort size of this magnitude is not feasible and is a major challenge even at a single institution 25. Yet, this is the largest data set with genomic/molecular characterization of brain metastases to date.…”

Section: Discussionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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Integrative clinical genomics of metastatic cancer

Cited by 749 publications

References 44 publications

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability drives metastasis through a cytosolic DNA response

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

Profiles of brain metastases: Prioritization of therapeutic targets

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