DNA repair genes and prognosis in sporadic forms of urothelial carcinoma of the upper urinary tract

Abstract

Introduction: Lynch syndrome or hereditary nonpolyposis colorectal cancer is caused by mutations in DNA repair genes, known as mismatch repair (MMR) genes, and is associated with microsatellite instability. Urothelial carcinoma of the renal pelvis is also associated with this syndrome. These genetic abnormalities have been described in sporadic forms of upper tract urothelial carcinoma (UTUC).

Material and method: This was a descriptive study and survival analysis of a series of 80 patients with sporadic UTUC with no metastases at diagnosis (N0/Nx M0) treated exclusively with nephroureterectomy. We evaluated the expression of MMR genes (hMLH1, hPMS2, hMSH2 and hMSH6) in sections performed with tissue microarray (TMA) and their association with clinical-pathological parameters. We analyzed the prognostic value of the loss of expression of these genes in UTUC.

Results: We detected no loss of MSH2 or of MSH6, but there was a loss of MLH1 in 11 cases (13.8%) and of PMS2 in 21 cases (26.3%). The expression of hMLH1 and hPMS2 were strongly associated (P<.0001), and this phenotype expression entails significant clinical implications. The loss of MLH1 was associated with a low grade (P=.02). Loss of PMS2 was associated with a lower stage (P=.05), a pushing pattern with no invasive edges (P=.008) and less angiogenesis (P=.008). The inactivation of hPMS2 or hMLH1 is an independent protective factor (HR, 0.309) and, along with the histologic grade (HR, 5.561), defines the patients' prognosis.

Conclusion: In our experience, the inactivation of hPMS2 or hMLH1 is an independent marker of good prognosis and occurs in a quarter of sporadic UTUC cases. The immunohistochemical study of these patients can be used to assess the screening of hidden forms of Lynch syndrome.

Keywords: Carcinoma urotelial; DNA repair genes; Genes de reparación de ADN; Inestabilidad de microsatélites; MLH1; Microsatellite instability; PMS2; Prognosis; Pronóstico; Tracto urinario superior; Upper urinary tract; Urothelial carcinoma.