The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer.

Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p=0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p=0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p=0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p=0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p=0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p=0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients.

Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer.

The human androgen receptor (AR) gene possesses 2 trinucleotide repeats of CAG and GGN in exon 1. The CAG repeat corresponds to a polyglutamine tract in the N-terminal region of the receptor, that affects its transcriptional efficiency. The GGN repeat codifies for a polyglycine tract, and affects the amount of the AR protein transcribed. The endometrium contains ARs and the androgens have antiproliferative properties in cultured endometrial cancer (EC) cells. Larger CAG repeats of the AR gene give rise to a weaker transcriptional activity and have been found to be associated with endometrial carcinogenesis. The possible involvement of CAG and GGN tracts in the progression of EC is unknown. To study that possibility, we have genotyped both CAG and GGN polymorphisms of the AR gene in tumor tissue genomic DNA from a series of 204 consecutive patients with EC, and analyzed the results with regard to the pathological features and clinical outcome of patients. We classified the alleles as S (short median). The genotype with both S-CAG repeat alleles (SS-CAG) was more common in patients diagnosed at an early stage (41.6% SS-CAG vs 22.6% SL- and LL-CAG together, p = 0.048) and in tumors that did not invade the vascular space (43.0% SS-CAG vs 26.4% SL- and LL-CAG together, p = 0.034). The genotype with SS-GGN alleles was more common in well-differentiated tumors (41.2% SS-GGN vs 25.2% LS- and LL-GGN together, p = 0.017) and in endometrioid histological subtype tumors (35.3% SS-GGN vs 13.0% SL- and LL-GGN together, p = 0.034). When the genotypes of both repeats coexisting in each tumor specimen were taken into consideration, the relationship between the SS-CAG genotype and early stage remained only in the presence of the SS-GGN genotype (43.9% vs 0%, p = 0.01). No other associations were observed. In univariate survival analysis, patients with short alleles of both repeats (SS-CAG and SS-GGN genotypes simultaneously) had a lower risk of cancer-specific death (p = 0.032, mean follow-up: 63 months). Our data suggests that short CAG or GGN repeats of the AR gene are associated with a more benign condition of traditional prognostic variables in EC.