Molecular Basis of Disease

The two main types of urothelial carcinoma (UC) are papillary UC (pTa) and "flat" UC (pTis), also known as noninvasive carcinoma in situ. Approximately 75% to 80% of UC are papillary and approximately 20% to 25% are CIS. Papillary tumors tend to recur but not progress to invasive cancer. CIS is aggressive and tends to progress to muscle-invasive cancer.

UC tumorigenesis is a multistep process. Papillary UC are thought to arise from areas of urothelial hyperplasia or from urothelial papillomas. Although most papillary tumors are low-grade tumors that have little tendency to progress to invasive tumors, a small proportion are highgrade tumors that have significant potential to progress to invasive UC. Most invasive UC tend to arise through the following sequence of events: normal urothelium to dys-plasia to CIS to invasive cancer.

At the chromosomal level, DNA ploidy studies demonstrate that the majority of low-grade papillary tumors are diploid or near-diploid tumors, while the majority of highgrade papillary UC, CIS, and invasive UC (pTa tumors) are aneuploid tumors.1 By comparative genomic hybridization (CGH) studies, noninvasive papillary UC have relatively few chromosomal abnormalities except for loss of all or part of chromosome 9, while tumors with lamina propria invasion (pT1 tumors) have a high number of chromosomal gains and losses.2 The pTl tumors also have loss of all or part of chromosome 9 but have numerous additional chromosomal abnormalities, which include whole or partial chromosomal losses and gains. Fluorescence in situ hybridization (FISH) studies provide further evidence that low-grade pTa UC tumors have relatively few chromosomal abnormalities, while CIS, high-grade pTa, and invasive UC have a high frequency of chromosomal abnormalities.3

Microsatellite analysis (MA) has revealed that frequent sites of allelic imbalance (AI) in UC include 3p, 4p, 8p, 9p, 9q, 11p, 13q, 17p, and 18q.4-6 Regions with high rates of AI

are the sites of known or putative tumor suppressor genes. Many of the regions that show high rates of AI correspond to the areas of chromosomal gains and losses detected by CGH.

Two important molecular genetic alterations that contribute to UC tumorigenesis are mutational and epigenetic alterations that inactivate the P16 gene, the TP53 gene, or both. P16 loss is one of the earliest events in the development of both papillary and flat/invasive UC.2,6-8 Mutations that inactivate the TP53 gene appear to be found primarily in CIS and invasive UC and not low-grade papillary tumors and in part may be responsible for the aggressive behavior of these tumors.9,10 Other oncogenes and tumor suppressor genes that have been found to be mutated in a subset of UC include MYC, HRAS, and PTEN.

Defective DNA mismatch repair (MMR) is manifested as microsatellite instability (MSI) at >30% of microsatellite markers examined and in most cases is associated with a loss of expression of one of the DNA MMR proteins, hMSH2, hMLHl, hMSH6, or hPMS2. MMR is rarely observed in UC of the bladder but is found in approximately 20% to 30% of upper tract UC.11,12 The finding of defective MMR in an upper tract UC should prompt an investigation into the possibility that the patient may have hereditary nonpolyposis colorectal cancer (HNPCC) and a germline mutation of one of the DNA MMR genes.

Chromosomal instability (CIN) is present in invasive UC and CIS. It is likely that genes that maintain genomic stability are inactivated early during invasive UC tumorigen-esis. CIN drives tumorigenesis and tumor progression by accelerating the mutation rate in tumor cells.13 The genes responsible for CIN in invasive UC are not known, and the role of TP53 inactivation in CIN has been a matter of debate. pTa tumors show no evidence of CIN but, as noted above, tend to be diploid or near-diploid tumors with relatively few chromosomal alterations. Until recently, the genetic alterations known to contribute to the formation of low-grade pTa tumors have been restricted to chromosome 9 and P16 alterations. Most low-grade papillary UC and urothelial papillomas have missense mutations of the

Normal urothelium

FGFR3 activation P53 alterations?

Urothelial dysplasia

Urothelial hyperplasia/papilloma

P16 inactivation TP53 inactivation

P16 inactivation

Low-grade papillary urothelial carcinoma CIN and aneuploidization TP53 inactivation

High-grade papillary carcinoma Carcinoma in situ

Activation and inactivation CIN and aneuploidization of other onco9enes and Activation and inactivation of tumor suppressor 9enes other oncogenes and tumor ยป.

Invasive urothelial suppressor genes carcinoma

Figure 25-1. Genetic pathways for urothelial carcinoma tumorige-nesis. Noninvasive papillary tumors are characterized by early activating mutations of the FGFR3 gene, inactivating mutations or epigenetic alterations of the P16 gene, and a diploid or near-diploid DNA content. CIS and invasive tumors are characterized by early inactivating mutations within the TP53 and P16 genes, chromosomal instability (CIN),and an aneuploid DNA content. A small proportion of papillary tumors may acquire TP53 alterations or alterations of other as-yet unknown genes that cause invasive potential of these tumors.

Figure 25-1. Genetic pathways for urothelial carcinoma tumorige-nesis. Noninvasive papillary tumors are characterized by early activating mutations of the FGFR3 gene, inactivating mutations or epigenetic alterations of the P16 gene, and a diploid or near-diploid DNA content. CIS and invasive tumors are characterized by early inactivating mutations within the TP53 and P16 genes, chromosomal instability (CIN),and an aneuploid DNA content. A small proportion of papillary tumors may acquire TP53 alterations or alterations of other as-yet unknown genes that cause invasive potential of these tumors.

fibroblast growth factor 3 (FGFR3) gene, while mutations of this gene are less common in invasive UC and CIS.14

Taken together, the various studies suggest that there are two genetic pathways leading to the development of UC.2,7 One pathway leads to the formation of noninvasive papillary UC and the other to the development of CIS/invasive UC (Figure 25-1). The pathway for noninvasive papillary UC is characterized by the presence of FGFR3 mutations and/or chromosome 9 alterations and P16 inactivation. The pathway for invasive UC is characterized by early alterations in the TP53 and P16 genes, late alterations of other tumor suppressor genes and oncogenes, chromosomal instability, and aneuploidy. The genetic differences between noninvasive papillary and CIS/invasive tumors likely explain the markedly different behavior and prognosis of these tumors.15

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