Microsatellite analysis of chromosome 3p region in sporadic renal cell carcinomas

The etiology and progression of renal carcinomas (RCC) is still poorly understood. RCC have been classified into several pathological entities. The most frequent type, clear cell carcinoma, accounts for about 80% of sporadic RCC and shows several chromosome abnormalities documented both by conventional cytogenetics, loss of eterozygosity (LOH) and replication error (RER) studies. In 10 clear cell type sporadic RCC we evaluated LOH and RER using a set of 10 microsatellite markers covering the chromosome 3p region, which has been suggested for interstitial deletions. Electrophoresis was performed by automated sequencer ABI Prism 377 and data were analyzed with Genescan and Genotyper 2.5 softwares. We revealed allelic loss in 48,7% of informative microsatellites and a single case of RER. We found the highest LOH frequency in 3p25-26 region where maps Von Hippel-Lindau (VHL) oncosuppressor gene. In addition, DNA hypermethylation, an alternative mechanism of VHL gene silencing, was evaluated by methylation-specific PCR. However hypermethylation status was not detected in any of our tumor samples.     

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study

Background:

There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case–control studies suggested an association between short blood telomere length (TL) and increased RCC risk.

Methods:

We conducted a large population-based case–control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models.

Results:

Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001).

Conclusion:

These data do not support the hypothesis that blood TL is associated with RCC. This population-based case–control study is, to our knowledge, the largest investigation to date of TL and RCC.     

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Numerous peptide receptors are overexpressed in human cancer, permitting in vivo tumor targeting. Among such receptors, those for the neurotransmitter neuropeptide Y (NPY) are overexpressed in various tumors. Since NPY can play a role in the kidney, NPY receptor expression and/or endogenous production of peptides of the NPY family (NPY, PYY, PP) were evaluated in 40 renal cell carcinomas (RCCs) and 18 nephroblastomas. NPY receptor protein expression was investigated by in vitro autoradiography using (125)I-labeled PYY in competition with NPY receptor subtype-selective analogs. NPY, PYY and PP production was assessed immunohistochemically. Fifty-six percent of RCCs expressed the Y1 receptor subtype in moderate density, and 80% of nephroblastomas expressed Y1 and Y2 subtypes in moderate to high density. Y1 was also highly expressed in intratumoral blood vessels. In selected cases, NPY was observed in nerve fibers in close association with intratumoral blood vessels and in the vicinity of tumor cells, while no PYY or PP was detected immunohistochemically in these sites. NPY receptors on renal tumor cells and tumor blood vessels may therefore be the molecular targets of endogenous NPY released by intratumoral nerve fibers. With regard to clinical applications, NPY receptors may act as in vivo targets for receptor-directed therapy of RCCs and nephroblastomas for which alternative therapeutic approaches are still required.     

家族性肾透明细胞癌的遗传学研究现状

 家族性肾透明细胞癌主要包括遗传性癌综合征伴发的肾透明细胞癌和单纯家族聚集性肾透明细胞癌两类，其中遗传性癌综合征伴发的肾透明细胞癌有希佩尔-林道病（VHL）、胚系3号染色体易位的家系、结节性硬化综合征和Birt-Hogg-Dube综合征中的伴发肾癌，文章就家族性肾透明细胞癌的遗传学研究现状进行了概述。     

Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas

Background

Piwi-interacting RNAs (piRNAs) are small RNAs of 27–30 nucleotides mapping to transposons or clustering in repeat genomic regions. Preliminary studies suggest an important role in cancerogenesis. This study is the first one investigating their prognostic impact in clear cell renal cell cancer (ccRCC) patients.

Methods

Three piRNAs (piR-30924, piR-57125, and piR-38756) selected on the basis of initial piRNA microarray analyses were determined using RT-qPCR in non-metastatic (n = 76) and metastatic (n = 30) ccRCC tissue at the time of nephrectomy in comparison to normal renal tissue (n = 77) and tissue from distant ccRCC metastases (n = 13). Primary clinical end points were recurrence-free and overall survival.

Results

piR-57125 showed lower expression in metastatic than in non-metastatic tumors, whereas the expression of piR-30924 and piR-38756 increased in metastatic tumors. The higher expression of piR-30924 and piR-38756 as well as the lower expression of piR-57125 in metastatic primary tumors were significantly associated with tumor recurrence and overall survival. Multivariate Cox regression analyses revealed both piR-30924 and piR-57125 as independent prognostic predictors. This impact was even more pronounced in non-metastatic patients.

Conclusions

This study demonstrates that the expression levels of these piRNAs in primary non-metastatic and metastatic ccRCC tissue can serve as potential prognostic biomarkers in combination with clinicopathological factors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0180-3) contains supplementary material, which is available to authorized users.     

Familial aggregation of urothelial cell carcinoma

Urothelial cell carcinoma (UCC) is not considered to be a familial disease. Familial clustering of UCC was described in several case reports, however, some with an extremely early age at onset suggesting a genetic component. Epidemiological studies yielded inconsistent evidence of familial UCC, possibly because of low power and the inability to adjust for strong confounding. In our study the existence of a familial subtype of UCC was evaluated, as well as familial clustering of UCC with other types of cancer. A population-based family case-control study was performed including patients newly diagnosed with UCC of the bladder, ureter, renal pelvis or urethra, between January 1995 and December 1997, in the southeastern part of the Netherlands. Information on the patients' first-degree relatives was collected by postal questionnaire and subsequent telephone calls. The patients' partners filled out a similar questionnaire on their relatives. All reported occurrences of UCC were verified using medical records. Disease occurrence among case-relatives and control-relatives was compared to obtain the familial risk. Random effect proportional hazards regression analyses were used to calculate this familial risk while adjusting for age, gender and smoking behavior. In 95 families of the 1,193 patients and in 36 families of the 853 partners at least 1 relative was diagnosed with UCC. This yielded an adjusted hazard ratio (HR) of 1.8 (95% CI: 1.3-2.7). An increased risk was also found for cancer of the hematolymphopoietic system (hazard ration = 1.9, 95% CI: 1.2-3.1) among case-relatives. These results indicate that UCC has a familial component with an almost 2-fold increased risk among first-degree relatives of patients with UCC, which cannot be explained by smoking. Future segregation analyses may indicate whether this clustering can be attributed to genetic susceptibility.     

Risk factors for renal cell carcinoma: results of a population-based case-control study

For a case-control study of risk factors for renal cell carcinoma, a mailed questionnaire was used to collect data on 518 cases and 1,381 population-based controls in Ontario, Canada. Active cigarette smoking increased risk twofold among males (odds ratio estimate [OR]=2.0, 95 percent confidence interval (CI)=1.4–2.8) and females (OR=1.9, CI=1.3–2.6). Passive smoking appeared to increase risk somewhat among nonsmokers (males: OR=1.6, CI=0.5–4.7; females: OR=1.7, CI=0.8–3.4). A high Quetelet index (QI) was associated with a twofold increase in risk in both sexes, although this was based on reported weight at age 25 years for males (OR=1.9, CI=1.2–3.1) and five years prior to data collection for females (OR=2.5, CI=1.4–4.6). Diuretic use was associated with significantly increased risk among females, but not among males. Phenacetin use increased risk, while acetaminophen use was not associated with altered risk, although few subjects used either compound. Multiple urinary tract infections increased risk, but only significantly in females (OR=1.9, CI=1.2–2.9). Our data indicate the need for further exploration of passive smoking and diuretics as risk factors, as well as elucidation of mechanisms by which high lifetime QI and frequent urinary-tract infections might increase risk of this cancer.Des Kreiger, Marrett, and Darlington are with the Department of Preventive Medicine and Biostatistics, University of Toronto, and Division of Epidemiology and Statistics, Ontario Cancer Treatment and Research Foundation, Canada. Dr Dodds is with the Keproductive Care Program of Nova Scotia, formerly of the Ontario Cancer Treatment and Research Foundation, Canada. Ms Hilditch is with the Ontario Cancer Treatment and Research Foundation Epidemiology Research Unit, University of Toronto, Canada. Address correspondence to Dr Kreiger Department of Preventive Medicine and Biostatistics, 12 Queen's Park Crescent West, 3rd Floor, McMurrich Building, University of Toronto, Toronto, Ontario M5S 1A8, Canada. This study was funded by a grant #01692 of the Ontario Ministry of Health.     

35例肾癌术后放疗的临床分析

目的：研究Ⅱ、Ⅲ期肾癌术后放疗的作用。方法：１９９２年１月－１９９５年１月,３５例Ⅱ和Ⅲ期肾癌行术后放疗。照射范围包括肾瘤床、肾蒂、主动脉旁及下腔静脉旁淋巴结区运用ＴＰＳ技术,采用直线加速器１８ＭＶＸ线照射,ＤＴ４５－５０Ｇｙ／５周。结果：失访２例按死亡处理,随访率９４．４％,全组无复发病例,三年及五年生存率各为５７％（２０／３５）和４５．７％（１６／３５）。三年生存率Ⅱ期为６９．２％（９／１３）     

家族性多发肿瘤遗传一例临床分析

目的 肿瘤具有遗传性,提高家族性肿瘤遗传认识的重要性,有利于对具有肿瘤家族史患者的早发现与早治疗.本文报告1例乳腺癌导管原位癌病例,同时介绍该病例肿瘤多发家系.方法 分析南昌市第三医院2015-09-15收治的1例无肿块触及的乳腺癌患者临床资料及肿瘤家族病史.结果 患者经乳腺摄影检查片示右乳外上方呈簇状泥沙样钙化集聚,术后病理提示乳腺导管原位癌(高级别).该家系4代28人,11例(39.3％)癌症患者,其中肺癌2例,结直肠癌2例,胃癌1例,肝癌1例,膀胱癌1例,子宫内膜癌1例,乳腺癌1例,脑膜胶质瘤1例,肾母细胞瘤1例.结论 该家系肿瘤具有家族聚集现象,呈常染色体显性遗传.     

Disparate survival trends in histologic subtypes of metastatic non-small cell lung cancer: a population-based analysis

Erlotinib, bevacizumab, and pemetrexed improved survival of metastatic non-small cell lung cancer (mNSCLC) in clinical trials, but their benefits are restricted to non-squamous histology. We studied recent survival trends in mNSCLC subpopulations defined by histology and associated clinical factors correlating with adenocarcinoma or endothelial growth factor receptor mutations. Using the Surveillance, Epidemiology and End Results database, we calculated relative survival at 1 year from diagnosis for mNSCLC cases diagnosed in 2000-2011. Trends by histology, age, sex, race, prevalence of smoking or poverty, expressed as annual percent change (APC) using joinpoint regression, were compared by test of slope parallelism (P_par). Among 226,446 cases, 47% had adenocarcinoma, 20% squamous carcinoma, 6% other, and 27% unspecified histology. The proportion of cases designated as adenocarcinoma significantly increased after 2005. One-year survival increased from 23.5% in 2000 to 30.5% in 2010, significantly more for adenocarcinoma (APC, 3.3%) than squamous carcinoma (APC, 2.1%, P_par=0.0018). For patients with adenocarcinoma, these trends were significantly better for Asians than Whites (P_par=0.012) and for areas with fewer smokers (P_par=0.014). Such differences were not observed for squamous carcinoma (P_par=0.87 and 0.14, respectively). The absolute disparity in one-year survival between adenocarcinoma and squamous carcinoma increased from 1.6% in 2000 to 5.5% in 2010. The disparity between Asians and Whites increased from 5.2% to 13.1%, respectively. These data demonstrate that improvement in survival of mNSCLC since 2000 is now evident on a population scale. The superior increment for patients with adenocarcinoma, particularly among Asians and in communities with fewer smokers, suggests impact of the newly introduced, histology-specific agents, rather than better supportive care alone. Growing disparities between adenocarcinoma and squamous carcinoma highlight the needs to intensify research on treatment for subgroups that did not benefit from recent advances.     

Protein kinase C in human renal cell carcinomas: role in invasion and differential isoenzyme expression

The role of protein kinase C (PKC) in in vitro invasiveness of four different human renal cell carcinoma (RCC) cell lines of the clear cell type was investigated. Different PKC-inhibitors markedly inhibited invasiveness of the highly invasive cell lines, suggesting an invasion-promoting role of PKC in human RCC. Analysis of PKC-isoenzyme expression by protein fractionation and immunoblotting revealed that all cell lines expressed PKC-alpha, -epsilon, -zeta, -mu and -iota as known from normal kidney tissue. Interestingly, PKC-delta, known to be expressed by normal kidney epithelial cells of the rat, was absent on protein and RNA levels in all RCC cell lines investigated and in normal human kidney epithelial cells. PKC-epsilon expression levels correlated positively with a high proliferation activity, but no obvious correlation between expression levels of distinct PKC-isoenzymes and in vitro invasiveness was observed. However, by immunofluorescence microscopy, membrane localisation of PKC-alpha and PKC-epsilon reflecting activation of the enzymes, was associated with a highly invasive potential. In conclusion, our results suggest a role for PKC in invasion of human RCCs and might argue in favour of a particular role of PKC-alpha and PKC-epsilon. Our results further suggest that organ-specific expression patterns of PKC-isoenzymes are not necessarily conserved during evolution.     

Oncofetal protein IMP3: a novel molecular marker that predicts metastasis of papillary and chromophobe renal cell carcinomas

BACKGROUND: Whether an oncofetal protein, IMP3, can serve as a prognostic biomarker to predict metastasis for patients with localized papillary and chromophobe subtypes of renal cell carcinomas (RCCs) was investigated. METHODS: The expression of IMP3 in 334 patients with primary papillary and chromophobe RCC from multiple medical centers was evaluated by immunohistochemistry. The 317 patients with localized papillary and chromophobe RCCs were further evaluated for outcome analyses. RESULTS: IMP3 was significantly increased in a subset of localized papillary and chromophobe RCCs that subsequently metastasized. Patients with localized IMP3-positive tumors (n=33; 10%) were over 10 times more likely to metastasize (risk ratio [RR], 11.38; 95% confidence interval [CI], 5.40-23.96; P<.001) and were nearly twice as likely to die (RR, 1.91; 95% CI, 1.13-3.22; P=.016) compared with patients with localized IMP3 negative tumors. The 5-year metastasis-free and overall survival rates were 64% and 58% for patients with IMP3-positive localized papillary and chromophobe RCCs compared with 98% and 85% for patients with IMP3 negative tumors, respectively. In multivariable analysis adjusting for the TNM stage and nuclear grade, patients with IMP3-positive tumors were still over 10 times more likely to progress to distant metastasis (RR, 13.45; 95% CI, 6.00-30.14; P<.001) and were still nearly twice as likely die (RR, 1.95; 95% CI, 1.15-3.31; P=.013) compared with patients with IMP3-negative tumors. CONCLUSIONS: IMP3 is an independent prognostic biomarker that can be used to identify a subgroup of patients with localized papillary and chromophobe RCC who are at high risk for developing distant metastasis.     

Association between microvessel density and histologic grade in renal cell carcinomas

Angiogenesis seems to contribute to tumor growth and the development of metastases. There may be an association between the vascular density of individual tumors and their prognosis. In the present survey we studied 53 cases of renal cell carcinoma investigating possible relationship between histologic grade and microvessel density (MVD) measured by an image analysis system. According to our results MVD was significantly associated with the histologic grade, higher grades being accompanied with a higher MVD. Further studies are needed to investigate a possible connection of MVD with the prognostic role of grade in RCCs.     

Evolving classification of renal cell neoplasia

The development of consensus classifications for renal epithelial neoplasia in 1996 and 1997 led to the recognition of renal adenoma, renal oncocytoma and metanephric adenoma/adenofibroma as benign tumors and conventional (clear cell) renal cell carcinoma (RCC), papillary RCC, chromophobe RCC and collecting duct carcinoma as malignant morphotypes. While the overwhelming majority of renal adenomas and metanephric adenomas are benign, malignant transformation of both types have been described and genetic predictors of malignant transformation are as yet unknown. The main groups of malignant renal tumors are associated with characteristic genetic changes; conventional RCC (-3p), papillary RCC (+7, +17, -Y), chromophobe RCC (hypodiploid). Recent studies have also shown focal loss of heterozygosity of 3p segments in papillary and chromophobe RCC, indicating that 3p mutations are not confined to the conventional RCC morphotype and suggesting the presence of an important tumor suppressor gene at this site. Sarcomatoid metaplasia may occur in any morphotype and this is associated with a poor prognosis. More recently additional varieties of conventional RCC (multilocular cystic RCC), collecting duct carcinoma (medullary renal carcinoma) and papillary RCC (Types 1 and 2), each showing a characteristic morphology, have been recognized.     

Characteristics of the coexistence of melanoma and renal cell carcinoma

BACKGROUND:

Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association.

METHODS:

Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM + RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series).

RESULTS:

RCC was diagnosed concomitantly or after MM in 83% of patients in the MM + RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM + RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM + RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P = .005). Only 2 cyclin‐dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM + RCC series who also were members of MM‐prone families.

CONCLUSIONS:

The high aggregation of cancers among patients in the MM + RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A. Cancer 2010. © 2010 American Cancer Society.     

A whole-genome analysis of allelic changes in renal cell carcinoma by in-gel competitive reassociation

We applied a differential cloning procedure, the in-gel competitive reassociation (IGCR) method, to clone altered genomic sites from the whole genomes of renal cell carcinoma cells. After four rounds of IGCR, we obtained from two patients libraries enriched 1000- and 2500-fold for differential DNA fragments specific to allelic changes in renal cell carcinoma. In these libraries, we found differential fragments of single-copy sequences as well as repetitive sequences. The fragments exhibited allelic loss, restriction-fragment-length polymorphism, size changes, and changes in the copy number, and common allelic losses were also detected in the cancer tissues from several renal cell carcinoma patients. Some of the clones showed changes in the repeat length of microsatellites. One third (seven of 22) of the clones exhibiting these changes were mapped to chromosomes 8 or 9. Decreases in the copy numbers of mitochondrial DNA and satellite I were observed in 13 of 17 and seven of 16 renal cell carcinoma patients, respectively. This suggests that the IGCR method can be used to clone DNA fragments with various structural changes from the whole genomes of cancer tissues. Mol. Carcinog. 22:158–166, 1998. © 1998 Wiley-Liss, Inc.     

Metastasis of renal cell carcinoma to a meningioma

A case of metastatic renal cell carcinoma within an intracranial meningioma is presented. The pathological and radiological findings are discussed.