Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Cancer Discovery, Год журнала: 2018, Номер 8(12), С. 1548 - 1565

Опубликована: Окт. 15, 2018

Abstract Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining chest cavity. To expand our understanding MPM, we conducted comprehensive integrated genomic study, including most detailed analysis BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined novel subtype with TP53 SETDB1 mutations extensive loss heterozygosity. also report strong expression immune-checkpoint gene VISTA in epithelioid strikingly higher than other solid cancers, implications for immune response MPM its immunotherapy. Our findings highlight new avenues further investigation biology therapeutic options. Significance: Through study 74 MPMs, provide deeper determinants aggressive behavior, define heterozygosity, discovered MPM. See related commentary by Aggarwal Albelda, p. 1508. This article highlighted In Issue feature, 1494

Язык: Английский

---

Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial

Nature Medicine, Год журнала: 2019, Номер 25(5), С. 751 - 758

Опубликована: Апрель 22, 2019

Язык: Английский

---

Mechanisms and Implications of Metabolic Heterogeneity in Cancer

Cell Metabolism, Год журнала: 2019, Номер 30(3), С. 434 - 446

Опубликована: Сен. 1, 2019

Язык: Английский

---

Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations

Nature, Год журнала: 2017, Номер 545(7653), С. 229 - 233

Опубликована: Апрель 25, 2017

Язык: Английский

---

The rules and impact of nonsense-mediated mRNA decay in human cancers

Nature Genetics, Год журнала: 2016, Номер 48(10), С. 1112 - 1118

Опубликована: Сен. 12, 2016

Язык: Английский

---

G-quadruplexes: a promising target for cancer therapy

Molecular Cancer, Год журнала: 2021, Номер 20(1)

Опубликована: Фев. 25, 2021

DNA and RNA can fold into a variety of alternative conformations. In recent years, particular nucleic acid structure was discussed to play role in malignant transformation cancer development. This is called G-quadruplex (G4). G4 formation drive genome instability by creating mutations, deletions stimulating recombination events. The importance structures the characterization cells currently demonstrated breast samples. this analysis correlation between an increased intratumor heterogeneity identified. suggests that might allow stratification supports identification new personalized treatment options. Because stability their presence within most human oncogenic promoters at telomeres, are tested as therapeutic target downregulate transcription or block telomere elongation cells. To date, different chemical molecules (G4 ligands) have been developed aim structures. review we discuss compare function relevance for approaches impact on development three entities, which differ significantly amount type mutations: pancreatic cancer, leukemia melanoma. present promising strategy individually tumor could support future.

Язык: Английский

---

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Trends in Cell Biology, Год журнала: 2019, Номер 29(10), С. 820 - 834

Опубликована: Авг. 14, 2019

Homologous recombination (HR)-deficient tumors are hypersensitive to poly-(ADP)-ribose polymerase inhibitors (PARPi)-induced DNA damage. Therefore, PARPi have shown great promise in the clinic, but rates of pre-existing and acquired resistance high.Four main mechanisms been characterized, representing those that impact on (i) cellular availability inhibitor, (ii) activity abundance PAR chains, (iii) reactivation HR, (iv) replication fork protection.Loss 53BP1–RIF1–REV7–Shieldin axis, is involved non-homologous end-joining repair double-strand breaks, reactivates resection HR BRCA1-deficient cells, leading resistance. Shieldin seems shield broken ends by blocking access nucleases. The exact mechanism which controls needs be resolved.Studies large patient cohorts will need clarify clinical relevance different mechanisms. Furthermore, research drive future genetic screening factors guide therapy decisions. Poly-(ADP)-ribose (PARP) inhibition synthetic lethal with deficiency for homologous (HR), a pathway essential break repair. PARP (PARPi) therefore hold treatment disruptive mutations BRCA1/2 or other factors. Unfortunately, has proved major problem clinic. Knowledge about expanding quickly, revealing four alter drug availability, affect (de)PARylation enzymes, restore stability. We discuss how studies yielded important insights into regulation (DSB) protection, these could pave way novel options target vulnerabilities. Genomic instability one enabling characteristics tumor development [1.Hanahan D. Weinberg R.A. Hallmarks cancer: next generation.Cell. 2011; 144: 646-674Abstract Full Text PDF PubMed Scopus (24860) Google Scholar]. To maintain genomic integrity, cells equipped multiple wide variety lesions caused exogenous endogenous events. One particularly toxic lesion (DSB; see Glossary). This can ionizing irradiation genotoxic chemicals, also arise as an intermediate resolving stalled collapsed forks (replication instability) [2.Ait Saada A. et al.Preserving integrity competence via pathway.DNA Repair (Amst). 2018; 71: 135-147Crossref (0) If left unrepaired repaired incorrectly, DSBs give rise mutations, deletions, amplifications, chromosomal translocations, various outcomes such senescence, cell death, malignant transformation. Over 30 years ago, Marie-Claire King colleagues discovered linkage between familial early-onset breast cancer region 17q21 [3.Hall J.M. al.Linkage chromosome 17q21.Science. 1990; 250: 1684-1689Crossref now know gene affected BRCA1, this not only linked cases ovarian sporadic origins [4.Kandoth C. al.Mutational landscape significance across 12 types.Nature. 2013; 502: 333-339Crossref (1721) Scholar, 5.Martincorena I. Campbell P.J. Somatic mutation normal cells.Science. 2015; 349: 1483-1489Crossref (255) 6.Konstantinopoulos P.A. al.Homologous deficiency: exploiting fundamental vulnerability cancer.Cancer Discov. 5: 1137-1154Crossref (169) 7.Turner N.C. Signatures DNA-repair deficiencies cancer.N. Engl. J. Med. 2017; 377: 2490-2492Crossref (4) BRCA1 factor (HR) (see Box 1 more detailed overview DSB repair). Moreover, homozygous loss tolerated during human mouse embryonic [8.Evers B. Jonkers Mouse models BRCA2 past lessons, current understanding prospects.Oncogene. 2006; 25: 5885-5897Crossref (138) survival-dependency partially overcome concomitant p53 [9.Hakem R. al.Partial rescue Brca1 (5–6) early lethality p21 null mutation.Nat. Genet. 1997; 16: 298-302Crossref Importantly, mammary gland-specific genes show increased formation Indeed, samples, often co-occur – always TP53 10.Kringen P. al.TP53 carcinomas from carriers two distinct founder mutations; relation age at diagnosis survival.BMC Cancer. 2005; 134Crossref (16) Epigenetic silencing expression promoter hypermethylation another reducing activity, occur frequently [6.Konstantinopoulos 11.Shakeri H. al.Methylation analysis APC its relationship clinicopathological features.Clin. Lab. 2016; 62: 2333-2337Crossref (5) 12.Vos S. al.BRCA methylation versus BRCA germline mutation-related cancers.Breast Cancer Res. 19: 64Crossref In addition aberrations encoding many BRCA2, PALB2, RAD51, known tumors. All display severe result deregulated phenotype referred 'BRCAness' [13.Lord C.J. Ashworth BRCAness revisited.Nat. Rev. 110-120Crossref (287) Scholar].Box 1DNA Double-Strand Break RepairDSBs most cytotoxic because they cause full disruption chromosome. lead insertions, duplications, translocations. Cells (Figure I): canonical NHEJ (cNHEJ), alternative end joining (a-EJ), single-strand annealing (SSA).In mammalian cNHEJ frequent type [108.Mladenov E. Iliakis G. Induction double strand breaks: increasing spectrum pathways.Mutat. 711: 61-72Crossref (247) bound KU70/80 DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming DNA-PK complex, recruits ligation machinery XRCC4, ligase IV, XLF. requires no minimal end-processing, potentially small insertions deletions. plays role immune receptor diversification both V(D)J class-switch (CSR) mediated cNHEJ. core mentioned above, 53BP1 downstream RIF1, REV7, complex required efficient 2 information).In S G2, when occurs sister chromatid present, I). Upon extensive end-resection endo- exonucleases MRE11, CtIP, DNA2, EXO1, yielding 3′ single-stranded (ss)DNA overhangs, ssDNA stretch forms filaments RPA. Subsequently, RPA replaced RAD51 help BRCA2–PALB2 [109.Yuan S.S. al.BRCA2 radiation-induced assembly Rad51 vivo.Cancer 1999; 59: 3547-3551PubMed invades sequence present uses it template synthesis accurate several functions ranging activating enhancing recombinase [54.Bunting S.F. al.53BP1 inhibits Brca1-deficient breaks.Cell. 2010; 141: 243-254Abstract (810) 55.Bouwman rescues associated triple-negative BRCA-mutated cancers.Nat. Struct. Mol. Biol. 17: 688-695Crossref (520) 110.Zhao W. al.BRCA1–BARD1 promotes RAD51-mediated pairing.Nature. 550: 360-365Crossref Scholar].When compromised unavailable, employs error-prone a-EJ SSA some extent resection, characterized use microhomology [111.Roerink al.Polymerase theta-mediated replication-associated breaks elegans.Genome 2014; 24: 954-962Crossref (58) Scholar], dependent LIG3 POLQ. Loss deficiency, suggesting backup [112.Ceccaldi al.Homologous-recombination-deficient tumours Poltheta-mediated repair.Nature. 518: 258-262Crossref (213) 113.Mateos-Gomez al.Mammalian theta suppresses recombination.Nature. 254-257Crossref (190) larger stretches ERCC1 RAD52 [114.Bhargava al.Regulation genome maintenance.Trends 32: 566-575Abstract (62) Scholar] I).DSB choice tightly regulated throughout cycle restrict S/G2 phase. A CDK-specific phosphorylation event T847 CtIP enables cell-cycle phases [115.Huertas Jackson S.P. Human mediates control repair.J. Chem. 2009; 284: 9558-9565Crossref (259) addition, recruitment [57.Escribano-Diaz al.A cycle-dependent regulatory circuit composed 53BP1–RIF1 BRCA1–CtIP choice.Mol. Cell. 49: 872-883Abstract 63.Feng L. al.RIF1 counteracts BRCA1-mediated 288: 11135-11143Crossref (147) well interaction PALB2 [116.Orthwein suppression G1 cells.Nature. 528: 422-426Crossref necessary inhibited G1. S/G2-specific binding partner BARD1 unmethylated H4K20 new histones post-replicative chromatin [117.Nakamura K. al.H4K20me0 recognition BRCA1–BARD1 directs chromatids.Nat. Cell 2019; 21: 311-318Crossref association phase-specific exclude RIF1 association, thereby preventing [118.Chapman J.R. al.BRCA1-associated exclusion damage sites underlies temporal Sci. 2012; 125: 3529-3534Crossref (141) 119.Densham R.M. al.Human ubiquitin barriers resection.Nat. 23: 647-655Crossref Another inhibit KU-binding cyren, protecting overhangs [120.Arnoult N. G2 inhibitor CYREN.Nature. 549: 548-552Crossref (9) ensure activation takes place available. Remarkably, that, even 15–20% [121.Beucher al.ATM Artemis promote G2.EMBO 28: 3413-3427Crossref (291) indicates cycle-independent aspects may play choice, context complexity [122.Shibata al.Factors determining phase.EMBO 30: 1079-1092Crossref (256) (SSA). information). When HR-deficient renders highly sensitive damaging drugs platinum compounds, standard care decades. 2005, Bryant al. Farmer first described promising approach targeted BRCA1/2-deficient [14.Bryant H.E. al.Specific killing BRCA2-deficient poly(ADP-ribose) polymerase.Nature. 434: 913-917Crossref (2450) 15.Farmer al.Targeting defect mutant therapeutic strategy.Nature. 917-921Crossref (3206) family proteins post-translational PARylation substrate processes transcription PARP1 sensing (SSBs), recent data unligated Okazaki fragments trigger unperturbed S-phase [16.Hanzlikova al.The importance sensor replication.Mol. 71 (e313): 319-331Abstract block trap damaged 1). Such structures add effect posing insurmountable replisome [17.Murai al.Trapping PARP2 inhibitors.Cancer 72: 5588-5599Crossref (622) 18.Murai al.Stereospecific trapping BMN 673 comparison olaparib rucaparib.Mol. Ther. 13: 433-443Crossref (232) require functional resolve blocks resume progression, hence induce death trials explore using platinum-sensitive BRCA1/2-mutated showed [19.Fong P.C. al.Inhibition carriers.N. 361: 123-134Crossref (2335) 20.Mirza M.R. al.Latest evidence further cancer.Ann. Oncol. 29: 1366-1376Crossref Since 2014, FDA- and/or EMA-approved monotherapy combination (reviewed [21.Gourley al.Moving targeting response therapy.J. Clin. (Published online 13 May 2019. http://doi.org/10.1200/JCO.18.02050)Crossref Scholar]). Recently, Phase Ib trial encouraging results simultaneous chemical genetically proficient [22.Konstantinopoulos al.Olaparib alpha-specific PI3K alpelisib patients epithelial dose-escalation dose-expansion phase 1b trial.Lancet 20: 570-580Abstract chemically induced approaches open possibility treating types either deficient HR. Studies marred high 23.Rottenberg al.High sensitivity AZD2281 alone drugs.Proc. Natl. Acad. U. 2008; 105: 17079-17084Crossref (548) platinum-based chemotherapies strong predictor resistance, indicating probably share common [24.Fong al.Poly(ADP-ribose) inhibition: durable responses carrier correlating platinum-free interval.J. 2512-2519Crossref As vivo vitro studies, identified. These classified categories influence directly protection 2). review we knowledge improved our murine model tumors, majority displayed overexpression drug-efflux transporter (Abcb1a Abcb1b MDR1/P-gp, Abcg2) [23.Rottenberg mesenchymal carcinosarcomas epithelial-to-mesenchymal transition phenotypes especially accompanied Abcb1a/b [25.Jaspers J.E. al.BRCA2-deficient sarcomatoid exhibit multidrug resistance.Cancer 75: 732-741Crossref (18) was found topoisomerase I II (topotecan doxorubicin, respectively) 26.Rottenberg al.Selective induction chemotherapy conditional hereditary cancer.Proc. 2007; 104: 12117-12122Crossref Consequently, coadministration MDR1 tariquidar resensitized Overexpression ABCB1 observed PARPi-resistant line, reversed cotreatment verapamil elacridar [27.Vaidyanathan al.ABCB1 (MDR1) defines paclitaxel- olaparib-resistant cells.Br. 115: 431-441Crossref suggests upregulated chemotherapy-treated cancers translocations involving [28.Christie E.L. al.Multiple transcriptional fusions resistant high-grade serous cancer.Nat. Commun. 10: 1295Crossref

Язык: Английский

---

Effects of anthocyanins on the prevention and treatment of cancer

British Journal of Pharmacology, Год журнала: 2016, Номер 174(11), С. 1226 - 1243

Опубликована: Сен. 20, 2016

Anthocyanins are a class of water-soluble flavonoids, which show range pharmacological effects, such as prevention cardiovascular disease, obesity control and antitumour activity. Their potential effects reported to be based on wide variety biological activities including antioxidant; anti-inflammation; anti-mutagenesis; induction differentiation; inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest stimulating apoptosis or autophagy cancer cells; anti-invasion; anti-metastasis; reversing drug resistance cells increasing their sensitivity chemotherapy. In this review, the latest progress anticancer anthocyanins underlying molecular mechanisms is summarized using data from basic research in vitro vivo, clinical trials taking into account theory practice.

Язык: Английский

---

Genomic and phenotypic heterogeneity in prostate cancer

Nature Reviews Urology, Год журнала: 2020, Номер 18(2), С. 79 - 92

Опубликована: Дек. 16, 2020

Язык: Английский

---

Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium

Cell Reports, Год журнала: 2018, Номер 24(7), С. 1777 - 1789

Опубликована: Авг. 1, 2018

Highlights•Endometriosis and uterine endometrium exhibit cancer-associated somatic mutations•Clonal expansion of epithelial cells with mutations in endometriosis•Genomic architecture is heterogeneous•Single endometrial glands carry distinct genesSummaryEndometriosis characterized by ectopic endometrial-like epithelium stroma, which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic 82 normal samples isolated laser microdissection. In both samples, numerous were identified within genes frequently mutated endometriosis-associated cancers. KRAS epithelium, a higher mutant allele frequency (MAF) accompanied arm-level allelic imbalances. Analyses MAF, combined multiregional sequencing, illuminated spatiotemporal evolution the endometriosis genomes. 109 single found that each gland carried mutations, demonstrating heterogeneity genomic epithelium. Remarkable increases MAF suggest retrograde flow already harboring selective advantages at sites, leading development endometriosis.Graphical abstract

Язык: Английский

---