We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors. ' 2006 Wiley-Liss, Inc.Key words: BDII; endometrial adenocarcinoma; RNO10; 17p13.3; allelic imbalance; Tp53 mutation; tumor suppressor gene Endometrial cancer is the most frequently diagnosed female genital tract malignancy in the western world. 1 Endometrial adenocarcinoma (EAC) is the prevalent subtype, accounting for approximately 75% of the reported cases. 2 It has been clearly demonstrated that an inherited genetic predisposition plays a critical role in the development of many cases of EAC, as the risk for a woman to develop EAC is tripled when there is an affected firstdegree relative. 3,4 Molecular genetic analysis of uterine tumor biopsies have revealed alterations in a number of chromosomal regions harboring transforming genes, including tumor suppressor genes (e.g. TP53, PTEN and hMLH1) and oncogenes (e.g. K-RAS and c-ERBB2/neu). 1,5-9 However, the molecular genetic events underlying endometrial cancer tumorigenesis are still poorly understood.Females of the inbred BDII rat strain are genetically prone to spontaneously occurring hormone-related endometrial carcinoma, providing a suitable experimental model system for genetic analysis of inherited EAC in humans. 10,11 Cytogenetic and comparative genome hybridization (CGH) analyses of the tumors pointed to common deletions in the proximal part of rat chromosome 10 (RNO10) in the tumor material. 12 According to Knudson's two-hit theo...

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Cancer is known to be a genetic disease that is both polygenic and heterogeneous, in most cases involving changes in several genes in a stepwise fashion. The spectrum of individual genes involved in the initiation and progression of cancer is greatly influenced by genetic factors unique to each patient. A study of complex diseases such as cancer is complicated by the genetic heterogeneous background and environmental factors in the human population. Endometrial cancer (EC) is ranked fourth among invasive tumors in women. In Sweden, approximately 1300 women (27/100,000 women) are diagnosed annually. To be able to study the genetic alterations in cancer, the use of an animal model is very convenient. Females of the BDII strain are genetically predisposed to EC and 90% of female BDII rats develop EC during their lifetime. Thus, BDII rats have been used to model human EC with respect to the genetics of susceptibility and of tumor development. A set of rat EC tumors was analyzed using conventional cytogenetics and comparative genome hybridization (CGH). Chromosomal aberrations, i.e., gains, were found on rat chromosome 4 (RNO4). Using FISH analysis, we concluded that the Met oncogene and Cdk6 (cyclin-dependent kinase 6) were amplified in this set of EC tumors. The data from this investigation were used to analyze a set of human endometrial tumors for amplification of Cdk6 and Met. Our preliminary data are indicative for a good correlation between our findings in the BDII rat model for EAC and the situation in human EC. These data provide strong support for the use of animal model systems for better understanding and scrutinizing of human complex disease of cancer.

Endometrial adenocarcinoma (EAC) is the fourth leading cause of cancer death in women worldwide, but not much is known about the underlying genetic factors involved in the development of this complex disease. In the present work, we used 3 different algorithms to derive tree models of EAC oncogenesis from data on the frequencies of genomic alterations in rat chromosome 10 (RNO10). The tumor material was derived from progenies of crosses between the EAC susceptible BDII inbred rat strain and two non susceptible inbred rat strains. Data from allelic imbalance scans of RNO10 with microsatellite markers on solid tumor material and corresponding tissue cultures were used. For the analysis, RNO10 was divided into 24 segments containing a total of 59 informative microsatellite markers. The derived tree models show that genomic alterations have occurred in 11 of the 24 segments. In addition, the models provide information about the likely order of the alterations as well as their relationship with each other. Interestingly, there was a high degree of consistency among the different tree models and with the results of previous studies, which supports the reliability of the tree models. Our results may be extended into a general approach for tree modeling of whole genome alterations during oncogenesis. ' 2006 Wiley-Liss, Inc.Key words: oncogenesis; microsatellite markers; endometrial adenocarcinoma; tree model; allelic imbalance Carcinogenesis is a multi-step process, which develops through the accumulation of multiple genetic mutations. 1,2 In a normal cell, the first mutation usually results in limited expansion of a clone. One of the descendants of the clone acquires a second mutation, resulting in further loss of growth control, and each successive mutation provides a further growth advantage. Once a set of critical genetic alterations develops, the cancer cell proliferates in an uncontrolled manner and the progeny starts to accumulate seemingly random alterations. 3 Eventually, the developing tumor will become malignant, invade the surrounding normal tissue and metastasize to other tissues and organs. 4,5 The total number of mutations that are present in a tumor cell population is estimated to be as many as 10,000. 6 However, the pivotal mutations that make transformation of a single normal cell into a malignant derivative can be as few as 3-7. 5 Obviously, it would be very difficult to identify these primary causative mutations among a total of 10,000, the majority of which are random events resulting from genomic instability. Mathematical models provide a promising approach to resolve this puzzle.Early work on models of oncogenesis used simple path models. One example is the work of Vogelstein et al. 7 where the progression of colorectal cancer by a chain of 4 genetic events was described. Once the first of these events occurs, the probability of the second event increases, and when the second event occurs, the probability of the third increases, and so on. Unfortunately, attempts to find similar path models for o...