Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study☆

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study.

Materials and methods

Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability.

Results

Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAF ^V600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities.

Conclusions

Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

Highlights

•

≥32% of patients with unfavorable CUP carried a potentially targetable genomic alteration.
•

Ten clusters were identified with specific genomic alteration co-occurrences.
•

Results reveal the molecular heterogeneity of patients with unfavorable CUP.
•

Genomic profiling may potentially be used for informed treatment decision-making in CUP.

Related collections

Most cited references 33

Record: found
Abstract: found
Article: not found

Signatures of mutational processes in human cancer

Ludmil Alexandrov, Serena Nik-Zainal, David Wedge … (2015)

All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.

0 comments Cited 2238 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

COSMIC: the Catalogue Of Somatic Mutations In Cancer

John G Tate, Sally Bamford, Harry C Jubb … (2018)

Abstract COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC’s deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.

0 comments Cited 1609 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Zachary Chalmers, Caitlin Connelly, David Fabrizio … (2017)

Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.

0 comments Cited 1154 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

A. Krämer

Journal

Journal ID (nlm-ta): ESMO Open

Journal ID (iso-abbrev): ESMO Open

Title: ESMO Open

Publisher: Elsevier

ISSN (Electronic): 2059-7029

Publication date PMC-release: 02 November 2023

Publication date Collection: December 2023

Publication date (Electronic): 02 November 2023

Volume: 8

Issue: 6

Electronic Location Identifier: 102035

Affiliations

[1 ]Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig Maximilian University of Munich, Munich, Germany

[2 ]F. Hoffmann-La Roche Ltd, Basel

[3 ]Department of Pathology and Molecular Pathology, University Hospital Zurich, Zürich, Switzerland

[4 ]Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg

[5 ]Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany

[6 ]The University of Manchester and the Christie NHS Foundation Trust, Manchester, UK

[7 ]Foundation Medicine, Inc., Cambridge, USA

[8 ]Hospital de Sant Joan Despí-Moisès Broggi, ICO-Hospitalet, Barcelona, Spain

[9 ]Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia

[10 ]SUNY Upstate Medical University, Syracuse, USA

[11 ]Department of Clinical Pathology and Centre for Cancer Research, University of Melbourne, Victorian Comprehensive Cancer Centre, Melbourne, Australia

Author notes

[∗ ] Correspondence to: Prof. Alwin Krämer, Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Tel: +49-6221-42-1440 a.kraemer@ 123456Dkfz-Heidelberg.de

[☆]

Note: These analyses have been presented in part: Westphalen CB, Karapetyan A, Beringer A, et al. Baseline mutational profiles of patients (pts) with carcinoma-of-unknown-primary-origin (CUP) enrolled on to CUPISCO. Poster presentation at the European Society for Medical Oncology (ESMO) 2021 Virtual Congress, September 16-21. Poster #1804P.

[†]

Co-first authors.

[‡]

Present address: Takeda, Berlin, Germany.

Article

Publisher Item ID: S2059-7029(23)01276-0 Publisher ID: 102035

DOI: 10.1016/j.esmoop.2023.102035

PMC ID: 10774891

PubMed ID: 37922692

SO-VID: a0fd65c4-fd52-4c88-b5e9-f5b13372933f

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study☆

Read this article at

Abstract

Background

Materials and methods

Results

Conclusions

Highlights

Related collections

DrugRxiv

Most cited references 33

Signatures of mutational processes in human cancer

COSMIC: the Catalogue Of Somatic Mutations In Cancer

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 271

Cited by 2

Most referenced authors 1,004