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Genomic imbalances associated with acquired resistance to platinum analogues.

ABSTRACT: During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our comparison of three analogues has shown the most frequently observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by amplification of 5q (3/7). We have defined four minimal common overrepresented regions, two each on 4q and 6q, which are potential loci of genes associated with platinum analogue resistance. Additional consistent abnormalities appear to be associated with cell lines sharing specific resistance mechanisms. For example, amplification of 12q was observed in the CH1 lines made respectively resistant to JM216 and AMD473 in which increased DNA repair appears to be a major mechanism of resistance for both agents. Hence, these comparative genomic hybridization studies have identified distinct chromosomal aberrations which may correlate with defined mechanisms of resistance and contain hitherto unrecognized genes that may provide targets for future therapeutic intervention.

SUBMITTER: Leyland-Jones B

PROVIDER: S-EPMC1866663 | biostudies-literature | 1999 Jul

REPOSITORIES: biostudies-literature

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Genomic imbalances associated with acquired resistance to platinum analogues.

Leyland-Jones B B Kelland L R LR Harrap K R KR Hiorns L R LR

The American journal of pathology 19990701 1

During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our com ...[more]

PMID: 10393840

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Project description:BackgroundFetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth.MethodsWe used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR.ResultsAneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3.ConclusionsWe conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.

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Genomic imbalances associated with acquired resistance to platinum analogues.

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Genomic imbalances associated with acquired resistance to platinum analogues.

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