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Keywords:

  • c-myc;
  • 8q;
  • prognosis;
  • concordance;
  • mitogen-activated protein kinase;
  • sorafenib;
  • kidney cancer

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

BACKGROUND:

The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS).

METHODS:

The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated.

RESULTS:

Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015).

CONCLUSIONS:

Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c-MYC inhibitors or agents that target the MAPK/ERK (mitogen-activated protein kinase) pathway. Cancer 2012. © 2012 American Cancer Society.

Cytogenetic analysis has emerged as a powerful tool to predict progression and prognosis of clear cell renal cell carcinoma (CCRCC).1, 2 This subtype is classically associated with loss of chromosome 3p, which is present in more than 50% of cases.1, 3, 4 Tumors with loss of 3p and subsequently loss of the VHL (von Hippel-Lindau) tumor suppressor gene are associated with less advanced tumor stages and better survival.1, 3 In addition, recent cytogenetic studies indicate that deletions of 4p, 9p, and 14q are associated with more advanced tumors and poorer survival, with 9p deletions retaining as an independent prognostic factor when adjusting for tumor stage and grade.1, 2

Chromosome 8q harbors the proto-oncogene c-MYC, which may be up-regulated through gain of 8q and subsequently alter tumor biology through the mitogen-activated protein kinase (MAPK/ERK) pathway.5 Constitutive overexpression of c-MYC leads to uncontrolled cell proliferation, escape from immune surveillance, metastasis, and angiogenesis, which are in part due to the increased synthesis of platelet-derived growth factor, insulin-like growth factor, fibroblast growth factor, and vascular endothelial growth factor (VEGF).6, 7 Furthermore, targeting the MAPK/ERK pathway and c-MYC with sorafenib and specific c-MYC inhibitors has been a promising therapeutic approach.8, 9 In several malignancies, gain of 8q has been identified as an adverse prognostic factor,10-13 but there are no data in CCRCC.

At our institution, we perform routine cytogenetic analyses in a prospective fashion on most primary RCC specimens since 2001. Because the role of 8q gain in CCRCC is unknown, we aimed to evaluate its prevalence and to correlate the findings with clinicopathological variables and disease-specific survival (DSS).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Patient Selection and Classification

Since 2001, tumors of 673 patients undergoing radical or partial nephrectomy for suspected RCC were subjected to classical cytogenetic tumor analysis. For the current study, patients with benign, hereditary, and bilateral renal masses were excluded. Only CCRCCs were included (n = 436), because other subtypes show distinct cytogenetic changes, which may obscure the true role of a rare cytogenetic aberration.1, 14

Clinicopathological variables were abstracted from the prospectively maintained University of California Los Angeles Kidney Cancer Database and included age, sex, pathologic stage, tumor/node/metastasis (TNM) stage grouping, nuclear grade, pathological tumor size, and DSS. Surgical specimens were assessed by a small group of expert uropathologists. Pathologic tumor stage was assigned according to the 2009 TNM classification15 and nuclear grade according to Fuhrman et al.16 The extent of disease was assessed with computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis and a chest CT or radiography. A radionuclide bone scan and cranial CT/MRI scans were only performed if metastases were present elsewhere or if the patient was symptomatic. After surgery, patients were followed according to our risk-adjusted surveillance protocol, as described.17 After a median follow-up of 25 months, 55 patients had died from CCRCC. Institutional review board approval was obtained for this study.

Cytogenetic Analysis

The detailed protocol of our cytogenetic studies has been published.1 In brief, viable tumor samples were collected immediately after surgery and minced into pieces 2 to 3 mm in thickness. After tissue dissociation with collagenase II (Worthington Biochem, Freehold, NJ), cells were washed and subsequently cultured in Roswell Park Memorial Institute 1640 medium supplemented with 20% fetal bovine serum and 1% penicillin/streptomycin. After harvesting, the cells were subjected to hypotonic treatment (KCl, 0.075 M) for 30 minutes at 37°C and fixed in methanol and acetic acid (3:1). Chromosomes were banded using the G-Bands by Pancreatin using the Giemsa technique. Twenty metaphases were investigated and analyzed in accordance with the International Standing Committee on Human Cytogenetic Nomenclature.18

Analyses were not possible due to culture failure in 43 of the 436 CCRCCs, leaving 393 with cytogenetic information. The 336 tumors (85%) with abnormal karyotype represent the reported cohort.

Statistical Analysis

Continuous data are presented as median and interquartile range, and categorical data are presented as number of patients (percentage of sample). Associations of 8q gain with categorical variables were analyzed with Fisher's exact tests for 2 × 2 contingency tables and chi-square tests for the remaining categorical variables with more than 2 possible values. Because Student t tests assume normal distribution, continuous variables were tested for normal distribution with Kolmogorov-Smirnov tests. Both age (P = .035) and tumor size (P < .001) were found to be non-normally distributed; thus, the nonparametric Wilcoxon rank-sum test was used to compare these continuous variables.

The primary focus of this study was to associate 8q gain with DSS. DSS was calculated from the date of surgery to the date of death from CCRCC or last contact. Survival probabilities were estimated with the Kaplan-Meier method. Survival functions were compared with log-rank tests, and univariable Cox proportional hazards models were fit to obtain a hazard ratio with the 95% confidence interval. Multivariable Cox proportional hazards models were fit to identify independent prognostic factors. The proportional hazard assumption was tested by the Schoenfeld test. To avoid overfit bias, T, N, and M classifications were not included as single variables, but summarized as TNM stage group.15 The predictive accuracy of prognostic models was assessed by the concordance (C) index. Harrell's U-statistic was computed to test whether C-indices between Cox models differ significantly. To further reduce overfit bias and to internally validate the accuracy estimates, the univariable and multivariable Cox models were subjected to 200 bootstrap resamples. All statistical tests were 2-sided and performed at a significance level of .05. The statistical software R, version 2.10.1, was used for all analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Clinicopathological and Cytogenetic Characteristics

A radical nephrectomy was performed in 136 patients (40.5%), whereas 200 (59.5%) had nephron-sparing surgery. Median age was 62 years. An Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 was assigned to 36.9% of patients. The median pathological tumor size was 5.5 cm. Lymph node and distant metastases were present in 7.4% and 26.5% of patients, respectively. Table 1 shows the descriptive statistics of the clinicopathological variables.

Table 1. Clinicopathological Characteristics and Associations With Gain of 8q
VariableTotal (n = 336)No Gain 8q (n = 308)Gain 8q (n = 28)P
  1. ECOG PS indicates Eastern Cooperative Oncology Group performance status; IQR, interquartile range; TNM, tumor/node/metastasis.

Age, y: median (IQR)62 (17)62 (17)63 (18).943
Sex, n (%)   .832
 Male234 (69.6)215 (69.8)19 (67.9)
 Female102 (30.4)93 (30.2)9 (32.1)
ECOG PS, n (%)   .542
 0212 (63.1)196 (63.6)16 (57.1)
 ≥1124 (36.9)112 (36.4)12 (42.9)
pT classification, n (%)   .101
 pT1-2210 (62.5)197 (64.0)13 (46.4)
 pT3-4126 (37.5)111 (36.9)15 (53.6)
pN classification, n (%)   .011
 pN0/Nx311 (92.6)289 (93.8)22 (78.6)
 pN+25 (7.4)19 (6.2)6 (21.4)
M classification, n (%)   .006
 M0247 (73.5)233 (75.6)14 (50.0)
 M189 (26.5)75 (24.4)14 (50.0)
TNM group - n (%)   .021
 I157 (46.7)151 (49.0)6 (21.4)
 II25 (7.4)23 (7.5)2 (7.1)
 III60 (17.9)54 (17.5)6 (21.4)
 IV94 (28.0)80 (26.0)14 (50.0)
Nuclear grade, n (%)   .551
 Grade 1-2199 (59.2)184 (59.7)15 (53.6)
 Grade 3-4137 (40.8)124 (40.3)13 (46.4)
Tumor size, cm: median (IQR)5.5 (5.4)5.2 (5.3)7.4 (4.6).030

Gain of 8q was detected in 28 tumors (8.3%). Twelve tumors (42.9%) had unbalanced translocations, which involved the chromosomes 3p (n = 3), 3q (n = 2), 16q (n = 2), 1p (n = 1), 2q (n = 1), 14q (n = 1), 15p (n = 1), and 19q (n = 1). In addition, 9 tumors (32.1%) showed trisomy 8, and 7 (25.0%) had i(8)(q10), which resulted in loss of 8p (pter-p10) and gain of 8q (q10-qter). Both gain of 8q and loss of 8p were found in 11 of the 28 tumors (39.3%, P = .010), whereas no association was found with loss of 3p (P = .228).

Gain of 8q and Clinicopathological Variables

Gain of 8q was associated with an increased risk of regional lymph node metastases (21.4% vs 6.2%; P = .011) and distant metastases (50.0% vs 24.4%; P = .006). Hence, TNM stage groups of tumors with 8q gain were higher (P = .021), and tumors with gain of 8q were significantly larger than tumors without gain of 8q (median size; 7.4 vs 5.2 cm, P = .030). With increasing pT classification, there was a trend toward a greater incidence of 8q gain, although this difference did not reach statistical significance (P = .101). No association was found with age (P = .943), sex (P = .832), ECOG PS (P = .542), or grade (P = .551). The associations between gain of 8q and standard clinicopathological variables are summarized in Table 1.

Gain of 8q and DSS

Gain of 8q was associated with a 3.22-fold increased risk of death from CCRCC (95% confidence interval, 1.76-5.90; P < .001; Table 1). For patients with gain of 8q versus those without gain of 8q, the 1- and 3-year DSS probabilities were 71.5% versus 90.8% and 49.4% versus 82.9%, respectively (Fig. 1). In univariable analysis, ECOG PS, TNM stage group, Fuhrman grade, and tumor size were also significant predictors of DSS (each P < .001, Table 1). In multivariable analysis, gain of 8q was retained as an independent prognostic factor (hazard ratio, 2.37; P = .006), in addition to TNM stage group (P < .001), ECOG PS (P = .004), and tumor size (P = .033) (Table 2). The C-index of a base model with the variables ECOG PS, TNM stage group, Fuhrman grade, and tumor size increased from 88.7% to 89.6% following inclusion of 8q gain. This increase in C-index was statistically significant (P = .0015).

thumbnail image

Figure 1. Kaplan-Meier disease-specific survival estimates are shown according to gain or no gain of chromosome 8q. Patients with gain of 8q had a 3.22-fold increased risk of death from clear cell renal cell carcinoma (P < .0001). HR indicates hazard ratio.

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Table 2. Univariable and Multivariable Cox Models Predicting Disease-Specific Survivala
 UnivariableMultivariable
  • a

    Gain of 8q was a significant prognostic factor in multivariable analysis. C-index of a base model (ECOG PS, TNM group, nuclear grade, tumor size) increased from 88.7% to 89.6% following inclusion of 8q gain in the multivariable model.

  • CI indicates confidence interval; ECOG PS indicates Eastern Cooperative Oncology Group performance status; TNM, tumor/node/metastasis.

VariableHR95% CIPHR95% CIP
ECOG PS4.232.37-7.54<.0012.401.32-4.38.004
TNM group4.522.82-7.25<.0013.872.36-6.33<.001
Nuclear grade3.642.06-6.42<.0011.090.58-2.04.792
Tumor size1.211.14-1.29<.0011.081.01-1.17.033
Gain of 8q3.221.76-5.90<.0012.371.28-4.41.006

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

This study shows that gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Multivariable analysis identified gain of 8q as an independent prognostic factor, which increased the predictive accuracy of a multivariable base model. Our findings may have important implications for postoperative risk group assessment and patient selection for targeted therapy.

In several malignancies, gain of 8q has been identified as an adverse prognostic factor.10-13 Ribeiro et al.10 showed in a FISH-based study on needle biopsies, that gain of 8q was associated with worse survival of patients with prostate cancer. Likewise, one study identified gain of 8q as a risk factor for progression following radical prostatectomy.11 Similarly to the current study, the authors found a correlation of 8p loss and 8q gain.11 By comparative genomic hybridization, Schleicher et al12 were able to show that gain of 8q leads to halved median survival time of patients with resected pancreatic cancer. In hepatoblastoma, this aberration was similarly identified as an adverse prognostic factor.13 This is the first to study to show this association in CCRCC. Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC.

The proto-oncogene c-MYC is located at the distal part of chromosome 8q, which was impacted by all aberrations leading to gain of 8q. A genome-wide analysis on 90 CCRCCs showed that c-MYC is consistently overexpressed in tumors with 8q24 amplification.19 Therefore, gain of 8q causes aberrant expression of c-MYC, which in turn can lead to uncontrolled cell proliferation, escape from immune surveillance, and growth factor production.6 c-MYC activity in CCRCC is further regulated via the HIF pathway, which itself plays a key role in progression of the disease.20-22 Taken together, our data suggest the up-regulation of this proto-oncogene, which subsequently leads to an aggressive tumor phenotype.

Additional data on c-MYC in CCRCC mirror the findings of this cytogenetic study. In terms of prevalence, Kozma et al23 found overexpression of c-MYC in 8.3% of specimens, a frequency which is in accordance with the current study. Similarly, Tang et al7 showed up-regulation of c-MYC and its target genes bcl2, cyclin D1, proliferating cell nuclear antigen, phosphoglycerate kinase 1, and VEGF. Interestingly, c-MYC up-regulation was found in >90% of specimens, indicating that other mechanisms than genetic aberrations or gene amplifications impact c-Myc activity.7 Kinouchi et al24 investigated expression of the c-Myc protein in 41 RCCs by immunohistochemistry. A significant association with grade was demonstrated, as c-Myc expression was found in 12% of grade 1, 81% of grade 2 and 100% of grade 3 tumors. Likewise, Lanigan et al25 were able to show that increasing c-Myc expression is associated with higher grades and pT classification. In a recent study based on fluorescence in situ hybridization analysis of 50 CCRCCs, however, no association of c-MYC copy numbers with grade or tumor size was demonstrated.26 One study found that higher c-Myc expression predicted diminished survival, although it did not provide independent prognostic information in multivariable analysis.25

Defining tumors with gain of 8q may assist in identifying patients for specific c-Myc inhibitors or agents targeting the MAPK/ERK pathway. Sorafenib inhibits raf kinase, which is a key protein of the MAPK/ERK pathway and an upstream of c-Myc. In recent years, c-Myc inhibitors such as 10058-F4 and approaches based on small interfering RNA have been promising as novel therapeutic agents in RCC.7, 27 In this regard, CCRCCs with gain of 8q and subsequent overexpression of c-Myc may be candidates for these approaches, because the MAPK/ERK pathway appears to be highly affected in these tumors. Gordan et al20 suggested that immunohistochemical expression of hypoxia-inducible factor 1 alpha (HIF1α) and HIF2α may be another helpful adjunct in this setting.

Identifying patients at high risk for progression and death from CCRCC remains a clinical challenge. Conventional clinicopathological factors such as TNM classification and grade provide prognostic information; however, combination of several independent prognostic factors in multivariable predictive models have increased their predictive accuracy.28 During the past decades, a wide variety of molecular prognostic markers have been identified, which further enhance the predictive accuracy of multivariable models.29, 30 Gain of 8q serves as another “proof of principle” that genetic information obtained from widely available technology is independently associated with CCRCC prognosis and provides additional information to standard prognostic factors.

Several limitations of this study merit consideration. Because the cytogenetic data were collected prospectively, the follow-up was relatively short. The subsequent low statistical power may explain why nuclear grade was not identified as an independent prognostic factor. Furthermore, the increase in C-index with inclusion of 8q gain was only 0.9% and thus relatively small, but may be greater in larger cohorts with longer follow-up. Because we included patients at all disease stages, analyses for particular subgroups were limited or could not be performed with appropriate statistical power. Some analyses such as the association of 8q gain with pT classification may only reach statistical significance with a larger number of patients. Furthermore, we did not evaluate c-MYC expression and were therefore not able to directly correlate the impact of 8q gain on c-MYC levels. However, data in a study of RCC support the overexpression of this particular gene in tumors with known 8q gain.31 Future studies will be needed to examine not only c-MYC, but also other genes located on chromosome 8q. Finally, external, prospective validation on data sets with longer follow-up is necessary before our results can be incorporated in clinical routine.

In conclusion, this study shows that gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is located on 8q, the current data suggest that tumors with gain of 8q may have unique molecular pathways activated, which are associated with an aggressive clinical phenotype. Defining tumors with gain of 8q may assist in identifying patients for specific c-MYC inhibitors or agents targeting the MAPK/ERK pathway.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosure.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES
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