Integrative genomic and transcriptomic analysis of leiomyosarcoma

Chudasama, Priya; Mughal, Sadaf S.; Sanders, Mathijs A.; Hübschmann, Daniel; Chung, Inn; Deeg, Katharina I.; Wong, Siao Han; Rabe, Sophie; Hlevnjak, Mario; Zapatka, Marc; Ernst, Aurélie; Kleinheinz, Kortine; Schlesner, Matthias; Sieverling, Lina; Klink, Barbara; Schröck, Evelin; Hoogenboezem, Remco M.; Kasper, Bernd; Heilig, Christoph E.; Egerer, Gerlinde; Wolf, Stephan; Kalle, Christof von; Eils, Roland; Stenzinger, Albrecht; Weichert, Wilko; Glimm, Hanno; Gröschel, Stefan; Kopp, Hans Georg; Omlor, Georg; Lehner, Burkhard; Bauer, Sebastian; Schimmack, Simon; Ulrich, Alexis; Mechtersheimer, Gunhild; Rippe, Karsten; Brors, Benedikt; Hutter, Barbara; Renner, Marcus; Hohenberger, Peter; Scholl, Claudia; Fröhling, Stefan

doi:10.1038/s41467-017-02602-0

Cited by 227 publications

(308 citation statements)

References 78 publications

(87 reference statements)

Supporting

Mentioning

283

Contrasting

Order By: Relevance

“…These include well-known cancer genes, such as CCND1 (25 tumors), CDK4 (25), MDM2 (23), SETDB1 (23), ERBB3 (11), ERBB2 (11), MYC (10), and MYCN (5). Thus, chromothripsis, perhaps with associated replication-based copy number gains 20,47 , may make a significant contribution to smallscale focal amplifications.…”

Section: Oncogene Amplification In Chromothripsis Regionsmentioning

confidence: 99%

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Cortés-Ciriano

Lee

et al. 2018

Preprint

View full text Add to dashboard Cite

SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

show abstract

Section: Oncogene Amplification In Chromothripsis Regionsmentioning

confidence: 99%

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Cortés-Ciriano

Lee

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Although STSs do not have a characterized defect in BRCA1/2, their genomics is complex in more than half of the cases, suggesting genomic instability and eventual possible deficiency in DNA damage repair and a high level of inherent DNA damage, as recently reported for leiomyosarcomas (Chudasama et al, 2018). Thus, STSs could be efficiently targeted with PARP inhibitors to drive cells to synthetic lethality.…”

Section: Introductionmentioning

confidence: 97%

PARP1 expression in soft tissue sarcomas is a poor‐prognosis factor and a new potential therapeutic target

et al. 2019

View full text Add to dashboard Cite

Soft tissue sarcomas (STSs) are aggressive tumors with few efficient systemic therapies. Poly(ADP‐ribose) polymerase‐1 (PARP1) inhibitors represent an emerging therapeutic option in tumors with genomic instability. The genomics of STSs is complex in more than half of cases, suggesting a high level of inherent DNA damage and genomic instability. Thus, STSs could be efficiently targeted with PARP inhibitors. Promising preclinical results have been reported, but few data are available regarding PARP1 expression in clinical samples. We examined PARP1 mRNA expression in 1464 clinical samples of STS, including 1432 primary tumors and 32 relapses, and searched for correlations with clinicopathological features, including metastasis‐free survival (MFS). Expression was heterogeneous across the samples, not different between primary and secondary tumors, and was correlated to PARP1 DNA copy number. In the 1432 primary tumors, the ‘PARP1‐high’ samples were associated with younger patients, more frequent locations at the extremities, superficial trunk and head and neck, more leiomyosarcomas and other STSs and less liposarcomas and myxofibrosarcomas, more grade 3, more high‐risk CINSARC tumors, and more ‘chromosomically instable’ tumors. They were associated with shorter MFS, independently of other significant prognostic features, including the CINSARC signature. We found a strong involvement of genes overexpressed in the ‘PARP1‐high’ samples in cell cycle, DNA replication, and DNA repair. PARP1 expression refines the prediction of MFS in STSs, and similar expression exists in secondary and primary tumors, supporting the development of PARP1 inhibitors.

show abstract

“…SNV and short indel calling was performed using in-house pipelines based on SAMtools mpileup (v0.1.19), BCFtools (v0.1.19), and Platypus (v0.8.1) as described previously [39] and updated more recently [40], with the exception of setting the mpileup threshold for minimum read mapping quality in the tumor to 30.…”

Section: Discussionmentioning

confidence: 99%

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient

et al. 2018

Self Cite

View full text Add to dashboard Cite

Background: In the field of breast cancer tumor biology, triple-negative breast cancer patients are the main focus of current clinical trials exploring the use of immune checkpoint inhibitors due to higher frequencies of somatic mutations, neoantigens, and resulting tumor-specific T-cell reactivity. Case Report: Here, we present the case of a 66-year-old woman with metastatic luminal breast cancer that rapidly responded to monotherapy with pembrolizumab, a monoclonal anti-PD-1 antibody. This patient obtained a partial clinical response within the first cycle of treatment and an ongoing durable complete remission after 12 weeks. Except for a transient immune-related thyreoiditis, there were no side effects observed offering remarkable quality of life to the patient. To evaluate the underlying mechanisms, we performed immunohistochemistry, explored the mutational landscape by whole-exome sequencing, and identified potential T-cell epitopes by prediction of neoantigens with high affinity binding to one of the patient's HLA. Briefly, we found a strong infiltration of CD8+ T cells without staining for PD-L1 in the tumor stroma. Exome sequencing revealed an enormous frequency of somatic and tumor-specific alterations, mainly C>T/G>A transitions. The mutational pattern was further linked to genome instability and deficient mismatch repair supported by the loss of MSH6 protein expression and therefore leading to susceptibility to immune checkpoint blockade. Conclusion: Within the overall goal to establish operating procedures for breast cancer immunotherapy, we propose to re-evaluate testing for deficient mismatch repair and to further intensify the search for biomarkers predictive for the success of immune checkpoint modulation including all tumor biologic subtypes of breast cancer.

show abstract

Integrative genomic and transcriptomic analysis of leiomyosarcoma

Cited by 227 publications

References 78 publications

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

PARP1 expression in soft tissue sarcomas is a poor‐prognosis factor and a new potential therapeutic target

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient

Contact Info

Product

Resources

About