Risk Factors For Development Of Renal Cell Carcinoma Research Articles

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

Renal cell carcinoma (RCC) represents a group of histologically similar neoplasms with significant intratumor and intertumor genetic heterogeneity. Recognized risk factors for RCC development include smoking, hypertension, obesity, as well as von Hippel-Lindau (VHL) disease. Inactivation of VHL, deregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression. Although the available results of both gene-gene and gene-environment analysis are quite heterogeneous, they clearly indicate that certain GST genotypes may play a role as risk modifiers, either individually or in combination with other Phase I or Phase II gene polymorphisms, as well as in subjects exposed to relevant substrates. Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. In addition to well established roles of GSTs in conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival. Indeed, there are evidence in favor of GST significance, not only in terms of risk for RCC development, but also with respect to progression and prognosis. So far, GSTM1-active genotype was confirmed to be an independent predictor of higher risk of overall mortality. Therefore, it is reasonable to assume that certain GST variants may assist in individual RCC risk assessment, as well as postoperative prognosis. Even more, GST profiling might contribute to development of personalized targeted therapy in RCC patients.

Renal cell cancer after kidney transplantation.

This study aims to identify modifiable risk factors for de novo renal cell carcinoma (RCC) after kidney transplantation in a matched-pair approach matching for unmodifiable factors. One thousand six hundred fifty-five adults who underwent kidney transplantation in the period 1 January 2000 to 31 December 2012 were analyzed. Patients with RCC after kidney transplantation were matched in a 1:2 ratio with those without RCC using the indication for transplantation, age at transplantation (± 10years), recipient sex (male/female), number of received transplants, living organ donor transplantation (yes/no), and time of follow-up in days as matching criteria. The paired t test was used to compare continuous variables and the Cochran-Mantel-Haenszel test for categorical variables. Multivariable conditional logistic regression modeling was used to identify independent risk factors for RCC. In matched-pair analysis, a total number of 26 incident cases with RCC after kidney transplantation could be matched. Post-transplant RCC was significantly associated with longer durations of pre-transplant hemodialysis (p = 0.007) and post-transplant immunosuppression with cyclosporine (p = 0.029) and/or mycophenolate mofetil (p = 0.020) and with larger proportions of post-transplant time on mycophenolate mofetil (p = 0.046) and/or prednisolone medication (p = 0.042). Multivariable conditional logistic regression modeling revealed a significant risk increasing multiplicative factor interaction between the duration of pre-transplant dialysis (years) and the time of prednisolone usage (percent/100). Cyclosporine A usage and mycophenolate mofetil usage were also revealed as independent, significant risk factors for RCC development. Longer pre-transplant dialysis, cyclosporine-based protocols and/or intensified immunosuppression with additional mycophenolate mofetil, and larger proportions of time of prednisolone treatment during follow-up increase de novo RCC risk.

Better survival of renal cell carcinoma in patients with inflammatory bowel disease.

Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population. A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991-2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes. 180 IBD patients with RCC were identified. Pancolitis (OR 1.8-2.5), penetrating Crohn's disease (OR 2.8), IBD related surgery (OR 3.7-4.5), male gender (OR 3.2-5.0) and older age at IBD onset (OR 1.0-1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression. IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease (mRCC) treated with sunitinib (Su).

e15058 Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese= BMI≥30 vs overweight=BMI 25-29.9 vs normal weight= BMI &lt;25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell vs non clear cell histology, initial diagnosis to Su tx initiation time, ≥ 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level &gt; 10, elevated alkaline phosphatase (AP), pre-tx neutrophil to lymphocyte ratio (NLR) &gt;3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and median Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. Results: Between 2004-2011, 244 pts with mRCC were treated with Su. 51 pts were active smokers, 58 obese, 62 diabetic, and 145 had pre-tx HTN. In the entire pt cohort, median PFS was 9 months (mos) and OS 21 mos. Factors associated with PFS were active smoking (HR 2.29, p= 0.003, median PFS 4 vs 10 mos in past smokers vs 12 mos in never smokers), non clear cell histology (HR 1.7, p=0.042), pre-tx NLR &gt;3 (HR 1.92, p&lt;0.0001) and the use of ASIs (HR 0.58, p=0.03). Factors associated with OS were were active smoking (HR 1.85, p= 0.018, median OS 11 vs 25 mos in past smokers vs 27 mos in never smokers), AP (HR 1.9, p=0.017), pre-tx NLR &gt;3 (HR 2.5, p&lt;0.0001), and liver mets (HR 1.86, p=0.021). BMI, DM, and pre-tx HTN were not associated with PFS or OS. Conclusions: Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease treated with sunitinib.

437 Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. Methods: We performed a multicentre retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese=BMI≥30 vs overweight=BMI 25-29.9 vs normal weight=BMI &lt;25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to Su tx, &gt; 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level &gt; 10 mg/dL, elevated alkaline phosphatase (AP), platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) &gt;3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and mean Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. Results: Between 2004-2011, 209 pts with mRCC were treated with Su. 40 pts were active smoker, 51 obese, 55 diabetic, and 122 had pre-tx HTN. In the entire pt cohort, median PFS was 8 months (mos) and OS 15 mos. Factors associated with PFS were active smoking (HR 2.5, p= 0.005, median PFS 4 vs 10 mos in past smokers vs 10 mos in never smokers), non clear cell histology (HR 1.8, p=0.023), pre-tx NLR &gt;3 (HR 0.2, p&lt;0.0001) and the use of ASIs (HR 1.66, p=0.028). Factors associated with OS were were active smoking (HR 2.1, p= 0.03, median OS 8.5 vs 18 mos in past smokers vs 18 mos in never smokers), AP (HR 1.76, p=0.049), pre-tx NLR &gt;3 (HR 0.294, p&lt;0.0001), and liver mets (HR 0.553, p=0.04). BMI, DM, and pre-tx HTN were not associated with PFS or OS. Conclusions: Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

Abstract A75: Preexisting kidney disorders and risk of renal cell carcinoma: Results from a population-based case-control study of Caucasians and African Americans

Abstract Background: In the United States, the incidence of renal cell carcinoma (RCC) is higher among African Americans (AA) than among Caucasians. However, few studies have investigated potential risk factors that may contribute to racial disparities in RCC incidence. Established risk factors for RCC include smoking, obesity, and hypertension. Beyond these factors the etiology of RCC remains largely unknown, though previous observations suggest that patients with end-stage renal disease on long-term dialysis may be at increased risk of developing RCC. Methods: We conducted an investigation of RCC risk in relation to pre-existing kidney disorders in a population-based case-control study of AAs and Caucasians in the metropolitan regions of Chicago and Detroit. Personal interviews were conducted to obtain information on history of kidney disorders and other covariates from 1,217 RCC cases (361 AAs and 856 Caucasians) and 1,235 controls (523 AAs and 712 Caucasians). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using sample weighted unconditional logistic regression models adjusted for age, sex, race, level of education, smoking status, body mass index, history of hypertension, family history of cancer, and study center. Analyses stratified by race and time since kidney disease diagnosis were also performed. Results: A statistically significant increased risk of RCC was observed among subjects who had been previously diagnosed with chronic renal failure (OR 4.7, 95% CI 2.2–10.1) or were on dialysis (OR 18.0, 95% CI 3.6–91.1). Stronger associations were observed among subjects who had renal failure or were on dialysis 10 or more years prior to RCC diagnosis. The association between chronic renal failure and RCC was considerably stronger among AAs than among Caucasians (ORs of 8.7 and 2.0, respectively; P-interaction=0.03). Among AAs, history of kidney stones, kidney cysts, and nephrotic syndrome were all associated with an elevated risk of RCC (OR≥2.0), though these findings were not statistically significant. Conclusions: The results of this large population-based study suggest that chronic renal failure and dialysis may be important risk factors for RCC development in both AAs and Caucasians. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A75.

Kidney Cancer

An estimated 38,890 Americans will be diagnosed with kidney cancer and 12,840 will die of this disease in the United States in 2006. Renal cell carcinoma (RCC) constitutes approximately 2% of all malignancies, with a median age at diagnosis of 65 years. Smoking and obesity are among the risk factors for RCC development, and tumor grade, local extent of the tumor, presence of regional nodal metastases, and evidence of metastatic disease at presentation are the most important prognostic determinants of 5-year survival. These guidelines discuss evaluation, staging, treatment, and management after treatment. For the most recent version of the guidelines, please visit NCCN.org