HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer

Al‐Kuraya, Khawla S.; Novotny, Hedvika; Bavi, Prashant; Siraj, Abdul K.; Uddin, Shahab; Ezzat, Adnan; Sanea, Nasser Al; Al‐Dayel, Fouad; Almana, Hadeel; Sheikh, Salwa S.; Mirlacher, Martina; Tapia, Coya; Simon, Ronald; Sauter, Guido; Terracciano, Luigi; Tornillo, Luigi

doi:10.1136/jcp.2006.038281

Cited by 105 publications

(71 citation statements)

References 16 publications

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“…In keeping with previous reports (18,20,21), we found a low rate of HER2 amplification (5.2%), albeit always correlated to a positive HER2 protein expression. Interestingly, we detected an inverse relationship between HER2 gene amplification and cetuximab efficacy.…”

Section: Discussionsupporting

confidence: 77%

“…Although EGFR amplification is readily identifiable by FISH analysis, in keeping with previous series (6,20,21), this genomic aberration was detected only in 2 (2.2%) patients, both responding to cetuximab. This seems to reflect the current knowledge on the DiFi cell line, which is unique among several colorectal cancer cell lines because it displays both high-level EGFR amplification and high levels of EGFR protein expression (22).…”

Section: Discussionmentioning

confidence: 77%

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Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Personeni¹,

Fieuws²,

Piessevaux

et al. 2008

Clinical Cancer Research

159

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Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN z2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of a variety of agents, including small inhibitory molecules and monoclonal antibodies (mAb). Two such mAbs, panitumumab and cetuximab, are active in metastatic colorectal cancer, but only subgroups of patients respond to these agents (1 -3) and reliable markers predictive of treatment benefit still need to be defined.Variations of gene copy numbers (GCN), either in terms of gains or losses, reflect the many different routes taken by individual tumors to disrupt/escape mechanisms governing normal cellular behavior. These genomic aberrations have been successfully investigated by fluorescence in situ hybridization (FISH) in a number of malignancies. Importantly, three recently published series have reported on enhanced sensitivity to anti-EGFR mAbs in colorectal cancer patients harboring an increase of mean EGFR GCN by FISH (4 -6). In most solid tumors, including non -small-cell lung cancer and colorectal cancer, the best characterized mechanisms underlying increased EGFR GCN are gene amplification and chromosome 7 polysomy (4 -7). Generally, amplification is representative of high-level genomic gain and it is readily identifiable by FISH. Conversely, polysomy mirrors variable degrees of chromosomal ga...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 77%

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Personeni¹,

Fieuws²,

Piessevaux

et al. 2008

Clinical Cancer Research

159

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“…A frequent genetic abnormality seen in colon cancer is the elevated expression of c-myc [4,9]. The importance of c-myc expression in colon cancer has been demonstrated in both studies of transgenic mice and clinical research [10,11]. Clinical studies have also indicated that c-myc is important in the development and progression of colon cancer, since over-expression of the oncogene was found in most colon cancer patients, correlated with poor prognosis [4].…”

Section: Introductionmentioning

confidence: 99%

The knockdown of c-myc expression by RNAi inhibits cell proliferation in human colon cancer HT-29 cells in vitro and in vivo

Zhang

Tian

2009

Cellular and Molecular Biology Letters

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Abstract:We investigated the effects of RNA interference-mediated silencing of the c-myc gene on celluar proliferation and apoptosis in human colon cancer HT-29 cells in vitro and in vivo. A small interfering RNA (siRNA) targeting c-myc was designed, the DNA template was synthesized, and the siRNA was obtained by in vitro transcription. After siRNA transfection into HT-29 and human neuroblastoma IMR-32 cells with Lipofectamine 2000 TM , the proliferation of the HT-29 and IMR-32 cells was assessed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetry, and Hoechst 33258 staining was used to observe cell apoptosis. Following gene transfer to HT-29 cells, the expression of c-myc mRNA was examined via reverse transcription polymerase chain reaction, and the level of the protein via Western blot assay. Growth curves were constructed and in vivo experiments were performed on nude mice to assess the effects of c-myc silencing on tumor growth. The c-myc expression in the tumor tissue was measured by reverse transcription polymerase chain reaction and subsequently by immunohistochemistry. Our paper demonstrates that the delivery of siRNA directed against c-myc not only efficiently down-regulated the expression of c-myc, inhibited the proliferation of HT-29 cells and induced apoptosis in vitro, but also suppressed the growth of colon cancer cells in vivo.

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“…1. These definitions were previously used in a multitude of studies investigating gene copy numbers by FISH (23,24).…”

Section: Translational Relevancementioning

confidence: 99%

Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer

Gammal¹,

Brüchmann²,

Zustin³

et al. 2010

Clinical Cancer Research

121

107

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Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown.Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization.Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT 2 cancers, 38.5%/9.8% of 379 pT 3a cancers, 43.5%/8.9% of 237 pT 3b cancers, 40.7%/14.8% of 27 pT 4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P < 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P < 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P < 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence.Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56-64. ©2010 AACR.Prostate cancer is the most frequently diagnosed malignancy and the second most frequent cause of cancerrelated death among western males (1).Currently, clinical prediction tools rely solely on clinical (clinical stage), serologic (prostate-specific antigen), and histologic variables (Gleason grading; ref. 2).Because the development and progression of cancer is driven by molecular alterations, the analysis of molecular features may eventually allow better prediction of the behavior of individual cancers.Alterations on the DNA level would be especially suitable as prognostic markers. DNA alterations have the advantage of being less vulnerable to perioperative and postoperative ischemia or fixation procedures than RNA or proteins (3, 4). Deletions of 8p and gains of 8q are among the most frequent genomic alterations in prostate cancer. Several studies have proposed a relationship between 8p−/8q+ with adverse histopathologic findings (5-11). Studies suggesting associations with prostatespecific antigen progression, however, were limited to <100 cancers (12)(13)(14). Whereas considerable evidence points toward a role of chromosome 8 changes in prostate cancer biology, it is also evident that much larger patient cohorts are now needed to further cl...

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HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer

Cited by 105 publications

References 16 publications

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

The knockdown of c-myc expression by RNAi inhibits cell proliferation in human colon cancer HT-29 cells in vitro and in vivo

Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer

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