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1.
Nature ; 629(8014): 1142-1148, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38588696

RESUMO

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadjuvante , Ftalazinas , Piperazinas , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Antraciclinas/uso terapêutico , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Resposta Patológica Completa , Ftalazinas/administração & dosagem , Ftalazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Estudos Prospectivos , Análise de Sobrevida , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/cirurgia , Adolescente , Adulto Jovem
2.
Nat Genet ; 30(4): 406-10, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11865300

RESUMO

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.


Assuntos
Carcinoma Papilar/genética , Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Leiomioma Epitelioide/genética , Leiomioma/genética , Neoplasias Uterinas/genética , Alelos , Cromossomos Humanos Par 1 , Éxons , Feminino , Fumarato Hidratase/metabolismo , Deleção de Genes , Genes Dominantes , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Masculino , Mutação , Linhagem , Recombinação Genética , Análise de Sequência de DNA
3.
Cancer Res ; 66(7): 3471-9, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16585170

RESUMO

Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization (CGH) for copy number changes and single-copy number polymorphism (SNP) microarrays for allelic loss (LOH). Many array-based CGH changes were not found by LOH because they did not cause true reduction-to-homozygosity. Conversely, many regions of SNP-LOH occurred in the absence of copy number change, comprising an average per cell line of 2 chromosomes with complete LOH; 1-2 terminal regions of LOH (mitotic recombination); and 1 interstitial region of LOH. SNP-LOH detected many novel changes, representing possible locations of uncharacterized tumor suppressor loci. Microsatellite unstable (MSI+) lines infrequently showed gains/deletions or whole-chromosome LOH, but their near-diploid karyotypes concealed mitotic recombination frequencies similar to those of MSI- lines. We analyzed p53 and chromosome 18q (SMAD4) in detail, including mutation screening. Almost all MSI- lines showed LOH and/or deletion of p53 and 18q; some near-triploid lines had acquired three independent changes at these loci. We found consistent results in primary colorectal cancers. Overall, the distributions of mitotic recombination and whole-chromosome LOH in the MSI- cell lines differed significantly from random, with some lines having much higher than expected levels of these changes. Moreover, lines with more LOH changes had significantly fewer copy number changes. These data suggest that CIN is not synonymous with copy number change and some cancers have a specific tendency to whole-chromosome deletion and regain or to mitotic recombination.


Assuntos
Instabilidade Cromossômica , Neoplasias Colorretais/genética , Perda de Heterozigosidade , Linhagem Celular Tumoral , Cromossomos Humanos Par 18/genética , Deleção de Genes , Dosagem de Genes , Humanos , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único
4.
Oncogene ; 24(1): 118-29, 2005 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-15531920

RESUMO

Microsatellite-stable, near-diploid (MSI-CIN-) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSI-CIN+ cancers. In order to address this question, we screened 23 MSI-CIN- colorectal cancers for gains and losses using array-based comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density. We compared our findings with those from a small set of MSI+CIN+ cancers, and with our reported data from MSI-CIN+ and MSI+CIN- cancers. We found no evidence of any form of genomic instability in MSI-CIN- cancers. At the level of the chromosome arm, the MSI-CIN- cancers had significantly fewer gains and losses than MSI-CIN+ tumours, but more than the MSI+CIN- and MSI+CIN+ lesions. The chromosomal-scale changes found in MSI-CIN- cancers generally involved the same sites as those in MSI-CIN+ tumours, and in both cancer groups, the best predictor of a specific change was the total number of such changes in that tumour. A few chromosomal-scale changes did, however, differ between the MSI-CIN- and MSI-CIN+ pathways. MSI-CIN- cancers showed: low frequencies of gain of 9p and 19p; infrequent loss of 5q and a high frequency of 20p gain. Overall, our data suggested that the MSI-CIN- group is heterogeneous, one type of MSI-CIN- cancer having few (< or =6) chromosomal-scale changes and the other with more (> or =10) changes resembling MSI-CIN+ cancers. At the level of individual clones, frequent and/or discrete gains or losses were generally located within regions of chromosomal-scale changes in both MSI-CIN- and MSI-CIN+ cancers, and fewer losses and gains were present in MSI-CIN- than MSI-CIN+ tumours. No changes by clone, which were specific to the MSI-CIN- cancers, were found. In addition to indicating differences among the cancer groups, our results also detected over 50 sites (amplifications, potential homozygous deletion and gains or losses which extended over only a few megabases) which might harbour uncharacterized oncogenes or tumour suppressor loci. In conclusion, our data support the suggestion that some MSI-CIN- carcinomas form a qualitatively different group from the other cancer types, and also suggest that the MSI-CIN- group is itself heterogeneous.


Assuntos
Carcinoma/genética , Aberrações Cromossômicas , Neoplasias Colorretais/genética , Diploide , Repetições de Microssatélites , Carcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
5.
J Pathol ; 205(1): 29-40, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15586366

RESUMO

In this study, 23 ovarian cancer cell lines were screened using array-comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density from throughout the genome. The most frequent recurrent changes at the level of the chromosome arm were loss of chromosome 4 or 4q, loss of 18q and gain of 20 or 20q; other recurrent changes included losses of 6q, 8p, 9p, 11p, 15q, 16q, 17p, and 22q, and gain of 7q. Losses of 4q and 18q occurred together more often than expected. Evidence was found for two types of ovarian cancer, one typically near-triploid and characterized by a generally higher frequency of chromosomal changes (especially losses of 4p, 4q, 13q, 15q, 16p, 16q, 18p and 18q), and the other typically near-diploid/tetraploid and with fewer changes overall, but with relatively high frequencies of 9p loss, 9q gain, and 20p gain. Multiple novel changes (amplifications, homozygous deletions, discrete regions of gain or loss, small overlapping regions of change and frequently changed clones) were also detected, each of which might indicate the locations of oncogenes or tumour suppressor loci. For example, at least two regions of amplification on chromosome 11q13, one including cyclin D1 and the other the candidate oncogene PAK1, were found. Amplification on 11q22 near the progesterone receptor gene and a cluster of matrix metalloproteinase loci was also detected. Other potential oncogenes, which mapped to regions found by this study, included cyclin E and PIK3C2G. Candidate tumour suppressor genes in regions of loss included CDKN2C, SMAD4-interacting protein and RASSF2.


Assuntos
Aberrações Cromossômicas , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Deleção Cromossômica , DNA de Neoplasias/genética , Feminino , Humanos , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ploidias
6.
Genes Chromosomes Cancer ; 34(4): 349-53, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12112523

RESUMO

The Knudson "two-hit" hypothesis has provided the rationale for studies that aim to identify tumor-suppressor genes by mapping regions of allelic loss (loss of heterozygosity, LOH). Although LOH has been found in practically all types of tumors, very few such projects have been successful in identifying their tumor-suppressor targets. The prime explanation for this failure is probably that researchers have, in general, been too credulous about the two-hit hypothesis, and too willing to ignore factors such as intratumor heterogeneity, contamination by normal cells, karyotypic complexity, homozygous deletions, gene dosage changes, and polymerase chain reaction artifacts. We suggest ways of minimizing these problems. Unfortunately, there is no guarantee that existing or newer methods, such as genomic microarrays and in situ single-nucleotide polymorphism analysis, will solve the difficulties of LOH analysis. The future prospects for LOH studies are, as ever, uncertain.


Assuntos
Análise Citogenética/métodos , Perda de Heterozigosidade/genética , Neoplasias/genética , Projetos de Pesquisa , Genes Supressores de Tumor , Humanos
7.
J Pathol ; 201(3): 389-94, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14595750

RESUMO

This study assessed whether low-level microsatellite instability (MSI-L) is a phenomenon specific to colorectal cancers or is also present in other tumour types. Breast (grade III ductal and lobular), endometrial and ovarian carcinomas, as well as colorectal cancers, were analysed for MSI-L using eight microsatellite markers. The markers were selected from a panel that had previously been shown to be sensitive for the detection of MSI-L in colorectal cancers. It was found that MSI-L was present in 30 of 87 (35%) colorectal cancers, 2 of 59 (3%) grade III breast carcinomas, 1 of 35 (3%) lobular breast cancers, 16 of 50 (32%) endometrial cancers, and 9 of 34 (26%) ovarian cancers. These results suggest that MSI-L is a very rare occurrence in breast carcinomas, but does occur as a real phenomenon in colorectal, endometrial, and ovarian carcinomas, which are all part of the hereditary non-polyposis colon cancer (HNPCC) syndrome. PCR artefact was also found to masquerade as MSI-L; criteria for the assessment of MSI-L are suggested to eliminate this problem.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias do Endométrio/genética , Repetições de Microssatélites/genética , Neoplasias Ovarianas/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Marcadores Genéticos/genética , Humanos , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase/métodos
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