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Research paper thumbnail of Supplementary Note from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Research paper thumbnail of Data from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

A breast cancer genome is a record of the historic mutagenic activity that has occurred throughou... more A breast cancer genome is a record of the historic mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation may be informative. Although driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically illuminating. This review is a chronicle of how the concept of mutational signatures arose and brings the reader up-to-date on this field, particularly in breast cancer. Mutational signatures have now been advanced to include mutational processes that involve rearrangements, and novel cancer biological insights have been gained through studying these in great detail. Furthermore, there are efforts to take this field into the clinical sphere. If validated, mutational signatures could thus form an additional weapon in the arsenal of cancer precision diagnostics and therapeutic stratif...

Research paper thumbnail of Supplementary Figure S3: Comparing mutational signatures from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Supplementary Figure S3: Comparing mutational signatures

Research paper thumbnail of Supplementary Figure S1: 13 mutational signatures from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Research paper thumbnail of Supplementary Table 2 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Details of 11 MMR deficient breast cancers.

Research paper thumbnail of Supplementary Table 4 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Detection of MMR deficient breast cancers in whole exome sequencing data (WES)

Research paper thumbnail of Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer

Nature Communications, Dec 8, 2022

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Nature

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper. An additional affiliation has been added for Husen M.

Research paper thumbnail of Author Correction: Patterns of somatic structural variation in human cancer genomes

Research paper thumbnail of Author Correction: Genomic basis for RNA alterations in cancer

Research paper thumbnail of Author Correction: The repertoire of mutational signatures in human cancer

Research paper thumbnail of Author Correction: Pan-cancer analysis of whole genomes

Research paper thumbnail of Author Correction: High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

Nature Communications

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. In the PCAWG Transcriptome Working Group, the affiliation 'BioForA, French National Institute for Agriculture, Food, and Environment (INRAE), ONF, Orléans, France' for Aurélien Chateigner was also missing. The original Article has been corrected. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of Author Correction: Divergent mutational processes distinguish hypoxic and normoxic tumours

Nature Communications

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of HRDetect : A mutational signature based predictor of BRCA 1 and BRCA 2 deficiency

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and ... more Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Germline and/or somatic mutations in BRCA1/BRCA2 in other cancer types also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2 deficient tumours have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns or mutational signatures were associated with BRCA1/BRCA2 dysfunction. We used a supervised lasso logistic regression model to identify six critically distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2 deficient samples. HRDetect identifies BRCA1/BRCA2 deficient tumours with 98.7% sensitivity (AUC 0.98). Application of this model in a cohort of 560 breast cancer patients with 22 known germline BRCA1/BRCA2 mutation carriers, allowed us to identify an additional 22 somatic BRCA1/BRCA2 null tumours and 47 tumours with functional BRCA1/BRCA2-deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers, and demonstrate efficacy on alternative sequencing strategies. Integrating all classes of mutational signatures thus reveals a larger proportion of breast cancer patients (of up to 22%) than hitherto appreciated (~1-5%) that could have selective therapeutic sensitivity to PARP-inhibition.

Research paper thumbnail of GAIA: Genomic Analysis of Important Aberrations

A current challenge in biology is the characterization of genetic mutations that occur as respons... more A current challenge in biology is the characterization of genetic mutations that occur as response to a particular disease. Development of array comparative genomic hybridization (aCGH) technology has been a very important step in genomic mutation analysis, indeed, it enables copy number measurement in hundreds of thousands of genomic points (called markers or probes). Despite the high resolution of aCGH, accurate analysis of these data is yet a challenge. In particular a major difficulty in mutation identification is the distinction between driver mutations (that play a fundamental role in cancer progression) and passenger mutations (which are random alterations with no selective advantages). This document describes classes and functions of GAIA (Genomic Analysis of Important Aberrations) package. GAIA uses a statistical framework based

Research paper thumbnail of Author Correction: A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies

Nature Cancer, 2020

In the version of this article initially published, the following statements were missing from th... more In the version of this article initially published, the following statements were missing from the Acknowledgements section: "We would also like to thank the International Cancer Genome Consortium for access to WGS primary cancer data. This work has been facilitated by Hartwig Medical Foundation (HMF) and the Center for Personalized Cancer Treatment (CPCT), which have generated and made available metastatic whole cancer genome data for this research. " The error has been corrected in the HTML and PDF versions of the article.

Research paper thumbnail of Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig

Nature Communications, 2020

The type and genomic context of cancer mutations depend on their causes. These causes have been c... more The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3–5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tu...

Research paper thumbnail of A Compendium of Mutational Signatures of Environmental Agents

Cell, 2019

If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Research paper thumbnail of Divergent mutational processes distinguish hypoxic and normoxic tumours

Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more like... more Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the...

Research paper thumbnail of Supplementary Note from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Research paper thumbnail of Data from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

A breast cancer genome is a record of the historic mutagenic activity that has occurred throughou... more A breast cancer genome is a record of the historic mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation may be informative. Although driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically illuminating. This review is a chronicle of how the concept of mutational signatures arose and brings the reader up-to-date on this field, particularly in breast cancer. Mutational signatures have now been advanced to include mutational processes that involve rearrangements, and novel cancer biological insights have been gained through studying these in great detail. Furthermore, there are efforts to take this field into the clinical sphere. If validated, mutational signatures could thus form an additional weapon in the arsenal of cancer precision diagnostics and therapeutic stratif...

Research paper thumbnail of Supplementary Figure S3: Comparing mutational signatures from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Supplementary Figure S3: Comparing mutational signatures

Research paper thumbnail of Supplementary Figure S1: 13 mutational signatures from Mutational Signatures in Breast Cancer: The Problem at the DNA Level

Research paper thumbnail of Supplementary Table 2 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Details of 11 MMR deficient breast cancers.

Research paper thumbnail of Supplementary Table 4 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Detection of MMR deficient breast cancers in whole exome sequencing data (WES)

Research paper thumbnail of Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer

Nature Communications, Dec 8, 2022

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Nature

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper. An additional affiliation has been added for Husen M.

Research paper thumbnail of Author Correction: Patterns of somatic structural variation in human cancer genomes

Research paper thumbnail of Author Correction: Genomic basis for RNA alterations in cancer

Research paper thumbnail of Author Correction: The repertoire of mutational signatures in human cancer

Research paper thumbnail of Author Correction: Pan-cancer analysis of whole genomes

Research paper thumbnail of Author Correction: High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

Nature Communications

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. In the PCAWG Transcriptome Working Group, the affiliation 'BioForA, French National Institute for Agriculture, Food, and Environment (INRAE), ONF, Orléans, France' for Aurélien Chateigner was also missing. The original Article has been corrected. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of Author Correction: Divergent mutational processes distinguish hypoxic and normoxic tumours

Nature Communications

In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper.

Research paper thumbnail of HRDetect : A mutational signature based predictor of BRCA 1 and BRCA 2 deficiency

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and ... more Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Germline and/or somatic mutations in BRCA1/BRCA2 in other cancer types also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2 deficient tumours have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns or mutational signatures were associated with BRCA1/BRCA2 dysfunction. We used a supervised lasso logistic regression model to identify six critically distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2 deficient samples. HRDetect identifies BRCA1/BRCA2 deficient tumours with 98.7% sensitivity (AUC 0.98). Application of this model in a cohort of 560 breast cancer patients with 22 known germline BRCA1/BRCA2 mutation carriers, allowed us to identify an additional 22 somatic BRCA1/BRCA2 null tumours and 47 tumours with functional BRCA1/BRCA2-deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers, and demonstrate efficacy on alternative sequencing strategies. Integrating all classes of mutational signatures thus reveals a larger proportion of breast cancer patients (of up to 22%) than hitherto appreciated (~1-5%) that could have selective therapeutic sensitivity to PARP-inhibition.

Research paper thumbnail of GAIA: Genomic Analysis of Important Aberrations

A current challenge in biology is the characterization of genetic mutations that occur as respons... more A current challenge in biology is the characterization of genetic mutations that occur as response to a particular disease. Development of array comparative genomic hybridization (aCGH) technology has been a very important step in genomic mutation analysis, indeed, it enables copy number measurement in hundreds of thousands of genomic points (called markers or probes). Despite the high resolution of aCGH, accurate analysis of these data is yet a challenge. In particular a major difficulty in mutation identification is the distinction between driver mutations (that play a fundamental role in cancer progression) and passenger mutations (which are random alterations with no selective advantages). This document describes classes and functions of GAIA (Genomic Analysis of Important Aberrations) package. GAIA uses a statistical framework based

Research paper thumbnail of Author Correction: A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies

Nature Cancer, 2020

In the version of this article initially published, the following statements were missing from th... more In the version of this article initially published, the following statements were missing from the Acknowledgements section: "We would also like to thank the International Cancer Genome Consortium for access to WGS primary cancer data. This work has been facilitated by Hartwig Medical Foundation (HMF) and the Center for Personalized Cancer Treatment (CPCT), which have generated and made available metastatic whole cancer genome data for this research. " The error has been corrected in the HTML and PDF versions of the article.

Research paper thumbnail of Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig

Nature Communications, 2020

The type and genomic context of cancer mutations depend on their causes. These causes have been c... more The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3–5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tu...

Research paper thumbnail of A Compendium of Mutational Signatures of Environmental Agents

Cell, 2019

If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Research paper thumbnail of Divergent mutational processes distinguish hypoxic and normoxic tumours

Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more like... more Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the...