Non–Small Cell Lung Cancer Exhibits Transcript Overexpression of Genes Associated with Homologous Recombination and DNA Replication Pathways

Saviozzi, Silvia; Ceppi, Paolo; Novello, Silvia; Ghio, P; Iacono, Marco Lo; Borasio, P.; Cambieri, Alberto; Volante, Marco; Papotti, Mauro; Calogero, Raffaele; Scagliotti, Giorgio Vittorio

doi:10.1158/0008-5472.can-08-2981

Cited by 63 publications

(45 citation statements)

References 33 publications

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“…Ordinarily, mammalian cells efficiently suppress recombination-mediated genomic rearrangements (13,14), but damage or loss of this control of recombination, combined with protracted recombination induction by environmental agents, may significantly impact the etiology of tumors in these organs. Evidence suggesting potential cancer etiology relevance for dysregulated recombination, particularly in the case of lung cancer, includes both the overexpression of recombination genes (15) and ATM defects commonly found in this tissue (16). Conversely, pediatric leukemia is thought to be driven by specific chromosomal events, rather than the gradual accumulation of malignant features caused by many years accumulating molecular genomic insults (17).…”

Section: Introductionmentioning

confidence: 99%

Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer

et al. 2009

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The gene that produces the precursor RNA transcript to the three largest structural rRNA molecules (rDNA) is present in multiple copies and organized into gene clusters. The 10 human rDNA clusters represent <0.5% of the diploid human genome but are critically important for cellular viability. Individual genes within rDNA clusters possess very high levels of sequence identity with respect to each other and are present in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homologous recombination. We recently developed a sensitive physical assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. To prove that this dysregulated recombination is a potential driving force of genomic instability in human cancer, we assayed the rDNA for structural rearrangements in prospectively recruited adult patients with either lung or colorectal cancer, and pediatric patients with leukemia. We find that over half of the adult solid tumors show detectable rDNA rearrangements relative to either surrounding nontumor tissue or normal peripheral blood. In contrast, we find a greatly reduced frequency of rDNA alterations in pediatric leukemia. This finding makes rDNA restructuring one of the most common chromosomal alterations in adult solid tumors, illustrates the dynamic plasticity of the human genome, and may prove to have either prognostic or predictive value in disease progression. [Cancer Res 2009;69(23):9096-104]

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Section: Introductionmentioning

confidence: 99%

Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer

et al. 2009

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“…These results are also consistent with the Saviozzi et al lung cancer study that found an association with Ku70 over-expression and more aggressive tumors [238]. Never disease free 22 (6) 31 (8) …”

Section: Relationships Of Cytosolic Ku Dna-binding Activities In Breasupporting

confidence: 90%

“…and Ku80 is associated with tumor progression in breast, lung, colorectal, skin, gastric and cervical carcinomas [238][239][240][241][242][243]. Ku levels in the majority of these studies were measured either by IHC or qRT-PCR.…”

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confidence: 99%

“…The percent survival at 60 months for patients with tumors exhibiting high Ku80 expression compared to those with low expression was 50% and 69%, respectively (p=0.087). Saviozzi et al correlated Ku80 gene expression levels in non-small cell lung cancer biopsies with overall survival of 50 patients [238]. Kaplan-Meier survival analysis showed that high Ku80 levels in lung lesions were associated with lower overall survival probabilities.…”

Section: Correlation Of Kumentioning

confidence: 99%

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Characterization of DNA-binding proteins as clinically relevant biomarkers of breast cancer behavior.

Kruer¹

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“…[17][18][19] Although little controversy exists regarding the association between ERCC1 and RRM1 with platinum and gemcitabine efficacy, there are recent reports of ERCC1 and RRM1 either not being significantly associated or potentially being inversely associated with the survival of NSCLC patients after a complete surgical resection. 20,21 Knowing the prognostic impact of both genes on the survival of patients not undergoing chemotherapy with a platinum agent and/or gemcitabine is important for the design and interpretation of clinical trials that incorporate both genes into a treatment decision algorithm, in particular if this treatment is given in a curative attempt in completely resected patients. Two clinical studies in patients with advanced NSCLC have already used this approach and reported a favorable disease response when treatment is selected based on gene expression.…”

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ERCC1 and RRM1 in the International Adjuvant Lung Trial by Automated Quantitative in Situ Analysis

Bepler

Olaussen

Vataire

et al. 2011

The American Journal of Pathology

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The excision repair cross completing group 1 gene product (ERCC1) and the regulatory subunit of ribonucleotide reductase (RRM1) have been reported as being prognostic of outcome and predictive of therapeutic efficacy in patients with non-small cell lung cancer. Routinely processed surgical specimens from 784 patients from the International Adjuvant Lung Trial were arrayed as tissue microarrays. In situ protein levels were scored with an automated, quantitative analysis system, dichotomized into high and low marker categories, and analyzed for associations with patients' characteristics, survival, and benefit from adjuvant chemotherapy. Scores for both markers were significantly associated with contributing center (P < 0.001) and skewed, with the bulk of scores being low. High scores were more frequent in women for ERCC1 and RRM1 and in older patients and those with adenocarcinoma for RRM1. Low ERCC1 scores indicated significant benefit from adjuvant chemotherapy [hazard ratio (HR) ‫؍‬ 0.73 for chemotherapy versus control, P ‫؍‬ 0.02]. Although all other survival associations were not statistically significant, low RRM1 scores trended to indicate benefit from adjuvant chemotherapy (HR ‫؍‬ 0.84, P ‫؍‬ 0.25), and ERCC1 scores were marginally prognostic of survival (HR ‫؍‬ 0.77 for high versus low scores, P ‫؍‬ 0.10). We conclude that contributing center and specimen quality substantially affect the levels of both markers. Future trials should incorporate the collection and processing of tumor specimens prospectively on standardized protocols to better reveal the impact of biomarkers on clinically relevant outcomes.

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Non–Small Cell Lung Cancer Exhibits Transcript Overexpression of Genes Associated with Homologous Recombination and DNA Replication Pathways

Cited by 63 publications

References 33 publications

Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer

Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer

Characterization of DNA-binding proteins as clinically relevant biomarkers of breast cancer behavior.

ERCC1 and RRM1 in the International Adjuvant Lung Trial by Automated Quantitative in Situ Analysis

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