Lead article
Patterns of specific genomic alterations associated with poor prognosis in high-grade renal cell carcinomas

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Abstract

A series of 13 sporadic renal cell carcinomas was analyzed for the specific chromosome rearrangements after serial xenografting into immunodeficient mice. Seven tumors displayed genetic traits of the conventional subtype and 5 showed genetic features of the papillary subtype. In all the xenografted conventional tumors, we observed loss of 3p, as well as loss of the 9p21 region and of the long arm of chromosome 14, both considered as markers of a poor prognosis. In the xenografted papillary tumors, a duplication of chromosome arm 8q was observed concomitant with the duplication of the 7q31 region. The association of the 7q31 and 8q22∼qter duplicated regions was also observed for one conventional tumor. The latency of tumor take was found to be reduced and the median time to passage statistically shorter for all tumors which presented the associated duplication of the 7q31 and 8q22∼qter regions. The proto-oncogene NOV (nephroblastoma overexpressed gene) maps to 8q24.1 and is overexpressed in some Wilms tumors. It could be an interesting candidate gene, since its level of expression and release in the culture medium was found to be increased in all of the fast growing tumors analyzed.

Introduction

Renal cell carcinomas (RCCs) represent 85–90% of all kidney tumors; the incidence is currently on a rising trend, especially in Europe and North America as compared to Asia and Africa. Frequently, the patients have metastases at the time of diagnosis or develop distant metastases following removal of the primary tumor 1, 2, 3. Histopathological classification separates the different types of RCCs into several categories of neoplasms, but classification can sometimes be difficult, partly due to the fact that histologic features may become highly anaplastic during tumor progression, and partly because differences between the histologic categories are sometimes ambiguous [4]. According to the Heidelberg classification [5] based on genomic alterations, two major groups were defined among the malignant neoplasms: (1) the conventional clear cell carcinomas characterized by the loss of the short arm of chromosome 3, the duplication of the 5q22 region and the deletion of chromosome arms 6q, 8p, 9p, and 14q (about 85% of cases); and (2) the papillary carcinomas characterized by trisomy of chromosomes 3q, 7, 8, 12, 16, 17, and 20 and loss of the Y chromosome (10–15% of cases). The identification of stable, characteristic genomic alterations, which occur during establishment and/or progression of the disease, is now considered as a useful approach to pinpoint new predisposing genes and candidate genes involved in tumor progression for both hereditary and sporadic forms of RCCs 2, 3, 6, 7. Thus, the new pathological classification can now take into account the results of such genomic analyses to complement the histopathological data in order to improve diagnosis and predict prognosis 8, 9.

We have previously shown that the tumorigenicity of a series of metastatic RCCs xenografted into immunodeficient (SCID) mice correlated with a poor clinical prognosis [10] and, in the xenografts established from papillary tumors, the main genomic alterations were maintained [11]. In a primary papillary RCC, a minor clone displayed minichromosomes carrying the minimal duplicated region overlapping the 7q31 band and containing the MET proto-oncogene. The MET gene was found to be present in the minimal overrepresented region from chromosome 7 common to three different papillary tumors 11, 12. We report here data showing a recurrence of associated chromosomal alterations specific to conventional or papillary RCC subtypes in xenografts obtained after a few passages into SCID mice. The results also disclose a relationship between some of these characteristic chromosomal alterations, the tumor growth rate of the xenografts in mice and a poor prognosis. The possible significance at the molecular level of some specific genomic duplications in the progression of RCCs is taken into consideration.

Section snippets

Histological features of tumors

Twenty RCCs were established as xenografts in SCID mice [10] and 13 were chosen for cytogenetic analysis. Six xenografts were derived from metastatic lesions (RCC-1, -3, -10, -43, -44, and -49) and seven from primary tumors (RCC-7, -16, -17, -28, -41, -45, and -47) with a Furhman nuclear grade from 1 to 3 [13].

Histological analysis was performed on acetic acid-formaline-ethanol fixed tissue specimens embedded in paraffin. In order to verify the relationship with the original tissue, the

Frequency of associated genomic alterations disclosed by xenografting

As shown in Table 1, 7 xenografted tumors displayed the genetic trait of the conventional subtype (loss of 3p), and 5 showed the genetic features of the papillary subtype (integrity of 3p and duplication of 7q). In all cases where a comparison between initial and xenografted tumor was possible (3 out of 7 conventional tumors and 4 out of 5 papillary tumors), the chromosomal abnormalities of each individual tumor were found to be maintained in the xenografts.

The main chromosomal abnormalities of

Discussion

In this report, we determine patterns of specific genomic anomalies found in xenografted conventional and papillary RCCs. Our results suggest that the identification of genetic alterations specifically associated with more aggressive tumor phenotypes could be useful for the diagnosis and predicting the prognosis of RCCs.

The minimal region deleted in the short arm of chromosome 3, in our conventional RCCs, was the 3p14∼pter region. This region includes the 3p25 region where the von Hippel-Lindau

Acknowledgements

This work was supported by the Association pour la Recherche sur le Cancer (grant no. 9105 to A. Bernheim and grant no. 9849 to B. Perbal), the Institut Gustave Roussy, the Ligue Nationale Contre le Cancer and the CNRS. L. Glukhova held a fellowship from the Fondation pour la Recherche Médicale and the Association pour le Recherche sur le Cancer.

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