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1.
Nat Commun ; 15(1): 4871, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38871738

ABSTRACT

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.


Subject(s)
Chromosomal Instability , ErbB Receptors , Lung Neoplasms , Mutation , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Mice , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Molecular Targeted Therapy/methods , Female , DNA Copy Number Variations , Male
2.
Nat Commun ; 15(1): 4653, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38821942

ABSTRACT

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Genetic Heterogeneity , Lung Neoplasms , Mice, Inbred NOD , Mice, SCID , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Animals , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Female , Exome Sequencing , Genomics/methods , Male , Xenograft Model Antitumor Assays , Heterografts , Disease Models, Animal , Aged , Middle Aged
3.
Nat Genet ; 56(1): 60-73, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38049664

ABSTRACT

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Animals , Mice , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Up-Regulation/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Cytidine Deaminase/genetics , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/metabolism
4.
Cell Rep ; 42(6): 112562, 2023 06 27.
Article in English | MEDLINE | ID: mdl-37245210

ABSTRACT

Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes-aldehyde dehydrogenase 1 family member 2 (ALDH1L2)-produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling.


Subject(s)
Breast Neoplasms , Formates , Oxidoreductases Acting on CH-NH Group Donors , Female , Humans , Breast Neoplasms/metabolism , Formates/metabolism , Methionine , NADP , Reactive Oxygen Species , Oxidoreductases Acting on CH-NH Group Donors/metabolism
5.
Cell ; 186(8): 1541-1563, 2023 04 13.
Article in English | MEDLINE | ID: mdl-37059064

ABSTRACT

Recent identification of oncogenic cells within healthy tissues and the prevalence of indolent cancers found incidentally at autopsies reveal a greater complexity in tumor initiation than previously appreciated. The human body contains roughly 40 trillion cells of 200 different types that are organized within a complex three-dimensional matrix, necessitating exquisite mechanisms to restrain aberrant outgrowth of malignant cells that have the capacity to kill the host. Understanding how this defense is overcome to trigger tumorigenesis and why cancer is so extraordinarily rare at the cellular level is vital to future prevention therapies. In this review, we discuss how early initiated cells are protected from further tumorigenesis and the non-mutagenic pathways by which cancer risk factors promote tumor growth. By nature, the absence of permanent genomic alterations potentially renders these tumor-promoting mechanisms clinically targetable. Finally, we consider existing strategies for early cancer interception with perspectives on the next steps for molecular cancer prevention.


Subject(s)
Neoplasms , Humans , Carcinogenesis , Cell Transformation, Neoplastic , Genomics/methods , Neoplasms/epidemiology , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Risk Factors
6.
Sci Transl Med ; 14(650): eabn3248, 2022 06 22.
Article in English | MEDLINE | ID: mdl-35731890

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low 2-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs and toxicity of therapy toward healthy hematopoietic cells. We studied the role of cyclin-dependent kinase regulatory subunit 1 (CKS1)-dependent protein degradation in primary human AML and healthy hematopoiesis xenograft models in vivo. Using a small-molecule inhibitor (CKS1i), we demonstrate a dual role for CKS1-dependent protein degradation in reducing patient-derived AML blasts in vivo and, importantly, depleting LSCs, whereas inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Proteomic analysis of responses to CKS1i in our patient-derived xenograft mouse model demonstrate that inhibition of CKS1 in AML leads to hyperactivation of RAC1 and accumulation of lethal reactive oxygen species, whereas healthy hematopoietic cells enter quiescence in response to CKS1i, protecting hematopoietic stem cells. Together, these findings demonstrate that CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.


Subject(s)
CDC2-CDC28 Kinases , Leukemia, Myeloid, Acute , Animals , CDC2-CDC28 Kinases/metabolism , CDC2-CDC28 Kinases/pharmacology , Hematopoiesis , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Myeloid, Acute/drug therapy , Mice , Neoplastic Stem Cells , Proteomics
7.
Cancer Discov ; 11(10): 2456-2473, 2021 10.
Article in English | MEDLINE | ID: mdl-33947663

ABSTRACT

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution.This article is highlighted in the In This Issue feature, p. 2355.


Subject(s)
APOBEC Deaminases/genetics , Breast Neoplasms/genetics , Carcinoma, Ductal/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Animals , Cell Line, Tumor , Chromosomal Instability , DNA Replication , Female , Humans , Mice
8.
Open Biol ; 11(1): 200247, 2021 01.
Article in English | MEDLINE | ID: mdl-33435818

ABSTRACT

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although advances are being made towards earlier detection and the development of impactful targeted therapies and immunotherapies, the 5-year survival of patients with advanced disease is still below 20%. Effective cancer research relies on pre-clinical model systems that accurately reflect the evolutionary course of disease progression and mimic patient responses to therapy. Here, we review pre-clinical models, including genetically engineered mouse models and patient-derived materials, such as cell lines, primary cell cultures, explant cultures and xenografts, that are currently being used to interrogate NSCLC evolution from pre-invasive disease through locally invasive cancer to the metastatic colonization of distant organ sites.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Models, Biological , Animals , Carcinogenesis , Disease Models, Animal , Humans , Neoplasm Metastasis , Neoplasm Recurrence, Local , Tumor Microenvironment
9.
Nature ; 587(7832): 126-132, 2020 11.
Article in English | MEDLINE | ID: mdl-32879494

ABSTRACT

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.


Subject(s)
Chromosomal Instability/genetics , Evolution, Molecular , Karyotype , Neoplasm Metastasis/genetics , Neoplasms/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 8/genetics , Clone Cells/metabolism , Clone Cells/pathology , Cyclin E/genetics , DNA Copy Number Variations/genetics , Female , Humans , Loss of Heterozygosity/genetics , Male , Mutagenesis , Neoplasm Metastasis/pathology , Neoplasms/pathology , Oncogene Proteins/genetics
10.
Nat Commun ; 11(1): 1792, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32286289

ABSTRACT

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat's antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.


Subject(s)
Cell Self Renewal , Histones/metabolism , Hydroxamic Acids/pharmacology , Neoplasms/metabolism , Neoplasms/pathology , Animals , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Self Renewal/drug effects , Cell Self Renewal/genetics , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Neoplasms/genetics , Recurrence
11.
Cell Rep ; 30(2): 481-496.e6, 2020 01 14.
Article in English | MEDLINE | ID: mdl-31940491

ABSTRACT

Loss of p53 function contributes to the development of many cancers. While cell-autonomous consequences of p53 mutation have been studied extensively, the role of p53 in regulating the anti-tumor immune response is still poorly understood. Here, we show that loss of p53 in cancer cells modulates the tumor-immune landscape to circumvent immune destruction. Deletion of p53 promotes the recruitment and instruction of suppressive myeloid CD11b+ cells, in part through increased expression of CXCR3/CCR2-associated chemokines and macrophage colony-stimulating factor (M-CSF), and attenuates the CD4+ T helper 1 (Th1) and CD8+ T cell responses in vivo. p53-null tumors also show an accumulation of suppressive regulatory T (Treg) cells. Finally, we show that two key drivers of tumorigenesis, activation of KRAS and deletion of p53, cooperate to promote immune tolerance.


Subject(s)
Myeloid Cells/metabolism , T-Lymphocytes, Regulatory/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Humans , Mice
12.
Cancer Res ; 78(23): 6529-6535, 2018 12 01.
Article in English | MEDLINE | ID: mdl-30420473

ABSTRACT

Chromosomal instability (CIN) is the result of ongoing changes in the number (aneuploidy) and structure of chromosomes. CIN is induced by chromosome missegregation in mitosis and leads to karyotypic diversity within the cancer cell population, thereby adding to intratumor heterogeneity. Regardless of the overall pro-oncogenic function of CIN, its onset is typically detrimental for cell fitness and thus tumors must develop CIN-tolerance mechanisms in order to propagate. There is overwhelming genetic and functional evidence linking mutations in the tumor suppressor TP53 with CIN-tolerance. However, the pathways leading to p53 activation following chromosome missegregation remain controversial. Recently, additional mechanisms have been identified in CIN-surveillance, resulting in a more complex network of pathways acting independently or in cooperation with p53. Tolerance might also be achieved by modifying aspects of the cancer cell physiology in order to attenuate CIN or by adaptation to the consequences of aneuploid karyotypes. In this review, we summarize the current knowledge about p53-dependent and -independent mechanisms of CIN-tolerance in cancer, the adaptations observed in CIN cells buffering CIN levels, its consequences for cellular homeostasis, and the potential of exploiting these adaptations in order to design new cancer therapies.


Subject(s)
Adaptation, Biological/genetics , Chromosomal Instability , Neoplasms/genetics , Animals , Biomarkers , Chromosome Segregation , Gene Dosage , Humans , Karyotype , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/therapy , Proteostasis , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
13.
Cell ; 173(3): 595-610.e11, 2018 04 19.
Article in English | MEDLINE | ID: mdl-29656894

ABSTRACT

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.


Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Alleles , Biomarkers, Tumor , Chromosomes , Clonal Evolution , Disease Progression , Evolution, Molecular , Female , Genetic Heterogeneity , Genetic Variation , Humans , Longitudinal Studies , Male , Middle Aged , Models, Statistical , Mutation , Neoplasm Metastasis , Phenotype , Phylogeny , Prognosis , Prospective Studies , Sequence Analysis, DNA
15.
Nature ; 545(7655): 446-451, 2017 04 26.
Article in English | MEDLINE | ID: mdl-28445469

ABSTRACT

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Lineage/genetics , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Evolution, Molecular , Lung Neoplasms/genetics , Neoplasm Metastasis/diagnosis , Neoplasm Recurrence, Local/diagnosis , Biopsy/methods , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Cell Tracking , Clone Cells/metabolism , Clone Cells/pathology , DNA Mutational Analysis , Disease Progression , Drug Resistance, Neoplasm/genetics , Early Detection of Cancer/methods , Humans , Limit of Detection , Lung Neoplasms/blood , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Multiplex Polymerase Chain Reaction , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Postoperative Care/methods , Reproducibility of Results , Tumor Burden
16.
Cancer Cell ; 31(1): 79-93, 2017 01 09.
Article in English | MEDLINE | ID: mdl-28073006

ABSTRACT

Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.


Subject(s)
Aneuploidy , Caspase 2/physiology , Colorectal Neoplasms/genetics , Cysteine Endopeptidases/physiology , DNA-Binding Proteins/physiology , Transcription Factors/physiology , Aged , Aged, 80 and over , Animals , BH3 Interacting Domain Death Agonist Protein/physiology , Caspase 2/analysis , Chromosome Segregation , Cysteine Endopeptidases/analysis , DNA-Binding Proteins/genetics , HCT116 Cells , Humans , Mice , Middle Aged , Mutation , Proto-Oncogene Proteins c-mdm2/physiology , Transcription Factors/genetics , Tumor Suppressor Protein p53/physiology
17.
Science ; 346(6206): 251-6, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25301630

ABSTRACT

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Genetic Heterogeneity , Genomic Instability , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , APOBEC-1 Deaminase , Carcinogens/toxicity , Carcinoma, Non-Small-Cell Lung/chemically induced , Cytidine Deaminase/genetics , Evolution, Molecular , Gene Dosage , Humans , Lung Neoplasms/chemically induced , Mutation , Neoplasm Recurrence, Local/genetics , Prognosis , Smoking/adverse effects , Translocation, Genetic , Tumor Cells, Cultured
18.
Genome Biol ; 15(8): 433, 2014 Aug 27.
Article in English | MEDLINE | ID: mdl-25159823

ABSTRACT

BACKGROUND: Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. RESULTS: We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. CONCLUSIONS: In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.


Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , von Hippel-Lindau Disease/genetics , Adult , Aged , Carcinoma, Renal Cell/pathology , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Exome , Gene Expression Regulation, Neoplastic , Genetic Heterogeneity , Germ-Line Mutation , Humans , MAP Kinase Signaling System , Male , Middle Aged , Models, Molecular , Phylogeny , Sequence Analysis, DNA , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/pathology
19.
Cancer Discov ; 4(2): 175-185, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24436049

ABSTRACT

UNLABELLED: The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution. SIGNIFICANCE: Our work sheds light on the importance of whole-genome­doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type.


Subject(s)
Chromosomal Instability , Neoplasms/genetics , Cell Line, Tumor , Colorectal Neoplasms/genetics , DNA Copy Number Variations , Humans , Neoplasms/mortality , Neoplasms/pathology , Phenotype , Ploidies , Polyploidy , Prognosis
20.
Cancer Cell ; 24(5): 617-30, 2013 Nov 11.
Article in English | MEDLINE | ID: mdl-24229709

ABSTRACT

RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110α expression or activity has comparable effects, albeit with greater toxicities.


Subject(s)
Adenocarcinoma/enzymology , Class I Phosphatidylinositol 3-Kinases/metabolism , Lung Neoplasms/enzymology , Proto-Oncogene Proteins p21(ras)/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Animals , Antineoplastic Agents, Hormonal/pharmacology , Class I Phosphatidylinositol 3-Kinases/chemistry , Class I Phosphatidylinositol 3-Kinases/genetics , Disease Progression , Humans , Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mutation , Protein Binding , Protein Interaction Domains and Motifs , Proto-Oncogene Proteins p21(ras)/metabolism , Pyridones/pharmacology , Pyrimidinones/pharmacology , Tamoxifen/pharmacology , Tumor Burden
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