Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer DOI Creative Commons

Erika Durinikova,

Nicole M. Reilly, Kristi Buzo

et al.

Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 28(17), P. 3874 - 3889

Published: July 26, 2022

Abstract Purpose: Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) emerging as promising therapeutic strategy in different solid tumors. The effectiveness DDR colorectal has not been extensively explored. Experimental Design: We challenged 112 cell models recapitulating the genomic landscape metastatic with ATM, ATR, CHK1, WEE1, DNA-PK inhibitors, parallel chemotherapeutic agents. focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers resistance, we analyzed at multiple levels highly sensitive or resistant these drugs. Results: found that around 30% cancers, including those carrying KRAS BRAF mutations unresponsive targeted agents, are least one inhibitor. By investigating potential ATRi, ATRi-sensitive cells displayed reduced phospho-RPA32 foci basal level, while ATRi-resistant showed increased RAD51 formation replication stress. Lack ATM RAD51C expression was associated ATRi sensitivity. Analysis mutational signatures HRDetect score identified subgroup models. Organoids derived from patients recapitulated findings obtained lines. Conclusions: In conclusion, subset cancers refractory current therapies could benefit pathways A composite biomarker involving foci, lack expression, well analysis be used likely respond ATRi.

Language: Английский

Targeting DNA damage response pathways in cancer DOI
Florian J. Groelly,

Matthew Fawkes,

Rebecca A. Dagg

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(2), P. 78 - 94

Published: Dec. 5, 2022

Language: Английский

Citations

475
Signatures of copy number alterations in human cancer DOI Creative Commons

Christopher D. Steele,

Ammal Abbasi, S. M. Ashiqul Islam

et al.

Nature, Journal Year: 2022, Volume and Issue: 606(7916), P. 984 - 991

Published: June 15, 2022

Abstract Gains and losses of DNA are prevalent in cancer emerge as a consequence inter-related processes replication stress, mitotic errors, spindle multipolarity breakage–fusion–bridge cycles, among others, which may lead to chromosomal instability aneuploidy 1,2 . These copy number alterations contribute initiation, progression therapeutic resistance 3–5 Here we present conceptual framework examine the patterns human that is widely applicable diverse data types, including whole-genome sequencing, whole-exome reduced representation bisulfite single-cell sequencing SNP6 microarray data. Deploying this 9,873 cancers representing 33 types from The Cancer Genome Atlas 6 revealed set 21 signatures explain 97% samples. Seventeen were attributed biological phenomena doubling, aneuploidy, loss heterozygosity, homologous recombination deficiency, chromothripsis haploidization. aetiologies four remain unexplained. Some harbour amplicon associated with extrachromosomal DNA, disease-specific survival proto-oncogene gains such MDM2 In contrast base-scale mutational signatures, no signature was many known exogenous risk factors. Our results synthesize global landscape by revealing diversity give rise these alterations.

Language: Английский

Citations

306
COSMIC: a curated database of somatic variants and clinical data for cancer DOI Creative Commons
Zbysław Sońdka,

Nidhi Bindal Dhir,

Denise Carvalho‐Silva

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D1210 - D1217

Published: Nov. 1, 2023

Abstract The Catalogue Of Somatic Mutations In Cancer (COSMIC), https://cancer.sanger.ac.uk/cosmic, is an expert-curated knowledgebase providing data on somatic variants in cancer, supported by a comprehensive suite of tools for interpreting genomic data, discerning the impact alterations disease, and facilitating translational research. catalogue accessed used thousands cancer researchers clinicians daily, allowing them to quickly access information from immense pool curated over 29 thousand scientific publications large studies. Within last 4 years, COSMIC has substantially expanded its utility adding new resources: Mutational Signatures catalogue, Mutation Census, Actionability. To improve accessibility interoperability, have received stable identifiers that are associated with their coordinates GRCh37 GRCh38, export files reduced redundancy been made available download.

Language: Английский

Citations

211
Mapping the genomic diaspora of gastric cancer DOI
Khay Guan Yeoh, Patrick Tan

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 22(2), P. 71 - 84

Published: Oct. 26, 2021

Language: Английский

Citations

127
Impact of risk factors on early cancer evolution DOI Creative Commons
Clare E. Weeden, William Hill, Emilia L. Lim

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1541 - 1563

Published: April 1, 2023

Language: Английский

Citations

71
Human papillomavirus genomics: Understanding carcinogenicity DOI Creative Commons
Chase W. Nelson, Lisa Mirabello

Tumour Virus Research, Journal Year: 2023, Volume and Issue: 15, P. 200258 - 200258

Published: Feb. 20, 2023

Human papillomavirus (HPV) causes virtually all cervical cancers and many at other anatomical sites in both men women. However, only 12 of 448 known HPV types are currently classified as carcinogens, even the most carcinogenic type - HPV16 rarely leads to cancer. is therefore necessary but insufficient for cancer, with contributing factors including host viral genetics. Over last decade, whole genome sequencing has established that fine-scale within-type variation influences precancer/cancer risks, these risks vary by histology race/ethnicity. In this review, we place findings context life cycle evolution various levels diversity: between-type, within-type, within-host. We also discuss key concepts interpreting genomic data, features genome; events leading carcinogenesis; role APOBEC3 infection evolution; methodologies use deep (high-coverage) characterize within-host variation, opposed relying on a single representative (consensus) sequence. Given continued high burden HPV-associated cancers, understanding carcinogenicity remains important better understanding, preventing, treating attributable infection.

Language: Английский

Citations

65
Tumour mutational burden: clinical utility, challenges and emerging improvements DOI
Jan Budczies, Daniel Kazdal, Michael Menzel

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(10), P. 725 - 742

Published: Aug. 27, 2024

Language: Английский

Citations

34
Geographic variation of mutagenic exposures in kidney cancer genomes DOI Creative Commons
S. Senkin, Sarah Moody, Marcos Díaz‐Gay

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8013), P. 910 - 918

Published: May 1, 2024

Abstract International differences in the incidence of many cancer types indicate existence carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to burden 1 . In clear cell renal carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do explain geographical variation its 2 Underlying causes can be inferred sequencing genomes cancers from populations with different rates detecting patterns somatic mutations. Here we sequenced 962 carcinomas 11 countries varying incidence. The mutation profiles differed between countries. Romania, Serbia Thailand, mutational signatures characteristic aristolochic acid compounds were present most cases, these rare elsewhere. Japan, signature unknown cause was found more than 70% cases less 2% A further ubiquitous exhibited higher loads kidney cancer. Known correlated consumption, no associated obesity or hypertension, suggesting non-mutagenic mechanisms action underlie factors. results this study multiple, geographically variable, mutagenic potentially affect tens millions people illustrate opportunities for new insights into causation through large-scale global genomics.

Language: Английский

Citations

31
Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer DOI Creative Commons
Axel K.M. Rosendahl Huber, Cayetano Pleguezuelos‐Manzano, Jens Puschhof

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 487 - 496.e6

Published: March 1, 2024

Co-culture of intestinal organoids with a colibactin-producing pks+ E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). Nissle 1917 (EcN) remains commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine mutagenicity EcN three CRC-derived strains an analytical framework based on sequence characteristic colibactin-induced mutations. All strains, including EcN, display varying levels mutagenic activity. Furthermore, machine learning approach attributing individual mutations to colibactin reveals that patients are diagnosed at younger age can induce specific APC mutation. These approaches allow sensitive detection ∼12% CRC genomes even whole exome sequencing data, representing crucial step toward pinpointing activity distinct strains.

Language: Английский

Citations

28
DNA mismatch and damage patterns revealed by single-molecule sequencing DOI

Mei Hong Liu,

Benjamin M. Costa,

Emilia C. Bianchini

et al.

Nature, Journal Year: 2024, Volume and Issue: 630(8017), P. 752 - 761

Published: June 12, 2024

Language: Английский

Citations

22