scholarly journals Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

2018 ◽  
Author(s):  
Stefan C. Dentro ◽  
Ignaty Leshchiner ◽  
Kerstin Haase ◽  
Maxime Tarabichi ◽  
Jeff Wintersinger ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Human Cancer ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Driver Gene ◽  
Cancer Type ◽  
Whole Genome ◽  
Sequencing Data ◽  
Cancer Types

SUMMARYIntra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

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

2018 ◽  
Author(s):  
Isidro Cortés-Ciriano ◽  
June-Koo Lee ◽  
Ruibin Xi ◽  
Dhawal Jain ◽  
Youngsook L. Jung ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
End Joining ◽  
Cancer Types ◽  
Non Homologous End Joining

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.

scholarly journals 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

2019 ◽  
Author(s):  
Sharon Christensen ◽  
Bastiaan Van der Roest ◽  
Nicolle Besselink ◽  
Roel Janssen ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Nucleotide Synthesis

Abstract5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

scholarly journals Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pauline A. J. Mendelaar ◽  
Marcel Smid ◽  
Job van Riet ◽  
Lindsay Angus ◽  
Mariette Labots ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Fragile Sites ◽  
Response To Treatment ◽  
Whole Genome Sequencing Data ◽  
Driver Gene ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genomic Landscape

AbstractIn contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.

scholarly journals A comprehensive characterization of cis-acting splicing-associated variants in human cancer

2017 ◽  
Author(s):  
Yuichi Shiraishi ◽  
Keisuke Kataoka ◽  
Kenichi Chiba ◽  
Ai Okada ◽  
Yasunori Kogure ◽  
...  
Keyword(s):  
Splice Site ◽  
Human Cancer ◽  
Intron Retention ◽  
Exon Skipping ◽  
Driver Mutations ◽  
Splice Sites ◽  
Sequencing Data ◽  
Cis Acting ◽  
Statistical Framework ◽  
Cancer Types

AbstractAlthough many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of these splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here we developed a statistical framework to identify SAVs disrupting or newly creating splice site motifs and applied it to sequencing data from 8,976 samples across 31 cancer types. We constructed a catalog of 14,438 SAVs, approximately 50% of which consist of SAVs disrupting non-canonical splice sites (including the 3rd and 5th intronic bases of donor sites) or newly creating splice sites. Smoking-related signature substantially contributes to SAV generation. As many as 14.7% of samples harbor at least one SAVs in cancer-related genes, particularly in tumor suppressors. Importantly, in addition to previously reported intron retention, exon skipping or alternative splice site usage more frequently affected these genes. Our findings delineate a comprehensive portrait of SAVs, providing a basis for cancer precision medicine.

scholarly journals Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types

2017 ◽  
Author(s):  
◽  
Claudia Calabrese ◽  
Natalie R. Davidson ◽  
Nuno A. Fonseca ◽  
Yao He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Specific Expression ◽  
Alu Elements ◽  
Cancer Types ◽  
Genome Analyses ◽  
Gene Alterations

AbstractWe present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called “bridged” fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

scholarly journals Pan-cancer whole-genome analyses of metastatic solid tumours

Nature ◽  
2019 ◽  
Vol 575 (7781) ◽  
pp. 210-216 ◽  
Author(s):  
Peter Priestley ◽  
Jonathan Baber ◽  
Martijn P. Lolkema ◽  
Neeltje Steeghs ◽  
Ewart de Bruijn ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Primary Tumour ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
Metastatic Tumour ◽  
Tumour Suppressor Genes ◽  
Whole Genome ◽  
Sequencing Data ◽  
Metastatic Lesions ◽  
Pan Cancer

Abstract Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

scholarly journals 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sharon Christensen ◽  
Bastiaan Van der Roest ◽  
Nicolle Besselink ◽  
Roel Janssen ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Nucleotide Synthesis ◽  
Mutational Pattern ◽  
Treatment Naïve ◽  
Strong Resemblance

Abstract 5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

scholarly journals Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer

2019 ◽  
Author(s):  
Kyungsik Ha ◽  
Masashi Fujita ◽  
Rosa Karlić ◽  
Sungmin Yang ◽  
Yujin Hoshida ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Progenitor Cells ◽  
Genome Sequencing ◽  
Primary Liver Cancer ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Cell Of Origin ◽  
Sequencing Data ◽  
Liver Cancers ◽  
Cancer Types

AbstractBackgroundPrimary liver tissue cancers display consistent increase in global disease burden and mortality. Identification of cell-of-origins for primary liver cancers would be a necessity to expand options for designing relevant therapeutics and preventive medicine for these cancer types. Previous reports on cell-of-origin for primary liver cancers was mainly from animal studies, and integrative research utilizing human specimen data was poorly established.MethodsWe analyzed a whole-genome sequencing data set for a total of 363 tumor and progenitor tissues along with 423 normal tissue epigenomic marks to predict the cell-of-origin for primary liver cancer subtypes.ResultsDespite the mixed histological features, the predicted cell-of-origin for mixed hepatocellular carcinoma / intrahepatic cholangiocarcinoma were uniformly predicted as a hepatocytic origin. Individual sample-level prediction revealed differential level of cell-of-origin heterogeneity depending on the primary liver cancer types, with more heterogeneity observed in intrahepatic cholangiocarcinomas. Additional analyses on the whole genome sequencing data of hepatic progenitor cells suggest these progenitor cells might not a direct cell-of-origin for liver cancers.ConclusionsThese results provide novel insights on the heterogeneous nature and potential contributors of cell-of-origin predictions for primary liver cancers.

scholarly journals Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

2021 ◽  
Vol 118 (36) ◽  
pp. e2007898118
Author(s):  
Marlinde L. van den Boogaard ◽  
Rurika Oka ◽  
Anne Hakkert ◽  
Linda Schild ◽  
Marli E. Ebus ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
High Frequency ◽  
Neuroblastoma Cells ◽  
Whole Genome Sequencing Data ◽  
Induction Treatment ◽  
Tumor Evolution ◽  
Copy Number Loss ◽  
Whole Genome ◽  
Sequencing Data

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH. Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.

scholarly journals Revisiting the tumorigenesis timeline with a data-driven generative model

2019 ◽  
Vol 117 (2) ◽  
pp. 857-864 ◽  
Author(s):  
Kamel Lahouel ◽  
Laurent Younes ◽  
Ludmila Danilova ◽  
Francis M. Giardiello ◽  
Ralph H. Hruban ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
Mechanistic Explanation ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Early Event ◽  
Driver Gene ◽  
Driver Genes ◽  
Fitness Advantage ◽  
Sequencing Studies ◽  
Cancer Types

Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.

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