A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina
ORGANISM(S): Homo Sapiens
SUBMITTER: Boston Children?s Hospital
PROVIDER: PRJEB45238 | EVA | 2021-05-27
REPOSITORIES: EVA
Similar Datasets
Project description:BACKGROUND:Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. RESULTS:Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. CONCLUSION:Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.
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Project description:PARP inhibitors are approved for the treatment of solid tumor types that frequently harbor alterations in the key homologous recombination (HR) genes, BRCA1/2. Other tumor types, such as lung cancer, may also be HR deficient, but the frequency of such cases is less well characterized. Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and their presence can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. We derived various HRD-associated mutational signatures from whole-genome and whole-exome sequencing data in the lung adenocarcinoma and lung squamous carcinoma cases from TCGA, and in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy, and in lung cancer cell lines. We found that a subset of the investigated cases, both with and without biallelic loss of BRCA1 or BRCA2, showed robust signs of HR deficiency. The extreme platinum responder case also showed a robust HRD-associated genomic mutational profile. HRD-associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. Consequently, lung cancer cases with HRD, as identified by diagnostic mutational signatures, may benefit from PARP inhibitor therapy.
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Project description:Analysis of human cancer genome sequences has revealed specific mutational signatures associated with BRCA1-deficient tumors, but the underlying mechanisms remain poorly understood. Here, we show that one-ended DNA double strand breaks (DSBs) converted from CRISPR/Cas9-induced nicks by DNA replication, not two-ended DSBs, cause more characteristic chromosomal aberrations and micronuclei in Brca1-deficient cells than in wild-type cells. BRCA1 is required for efficient homologous recombination of these nick-converted DSBs and suppresses bias towards long tract gene conversion and tandem duplication (TD) mediated by two-round strand invasion in a replication strand asymmetry. However, aberrant repair of these nick-converted one-ended DSBs, not that of two-ended DSBs in Brca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those in BRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated with BRCA1 deficiency in cancer and the underlying mechanisms.
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Project description:Genome-scale mutational signatures of aflatoxin in cells, mice and human tumor
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Project description:Initiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures.
2020-09-12 | GSE157845 | GEO
Project description:Initiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures.
2020-10-21 | GSE159680 | GEO
Project description:Initiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures.
2020-10-21 | GSE159679 | GEO
Project description:Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. However，in colorectal cancer (CRC), the role of HRD alterations is mostly unknown. This study aims to explore the the Efficacy and Safety of Fluzoparib combined with Irinotecan in the Second-line treatment of HRD alterations metastatic colorectal cancer.
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Project description:Although several proteogenomic analyses of high-grade serous ovarian cancer (HGSOC) have been conducted, these analyses are often dominated by tissues with high levels of tumor cell nuclei (purity), despite low purity being associated with worse outcome. We performed deep proteogenomic profiling of bulk tumor (BT) and laser microdissection (LMD) enriched tumor (ET) and stromal (ST) cell populations from 70 HGSOC patient tumors spanning a broad spectrum of purity. We identified a cluster of patients with longer progression free survival associated with increased immune signatures and validated proteins correlating with tumor infiltrating lymphocytes (TILs) in 65 tumors collected from an independent cohort of 12 HGSOC patients, as well as with overall survival in an additional cohort of 126 HGSOC patients. We identified that homologous recombination deficient (HRD) tumors express transcriptomic and proteomic pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts, including 69 HRD-positive HGSOC tumors. In summary, our proteogenomic analysis provides important new clinically relevant insights into HGSOC tumor cell populations, and have uncovered prognostic proteogenomic alterations correlating with TILs, low tumor purity, as well as expression alterations associated with HRD status and immune infiltration.
2024-03-15 | PXD045417 | Pride
Project description: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. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six 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 tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (?1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
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