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

Abstract

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 5 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 5 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 5 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 5 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 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 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. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

“…Furthermore, we observed that tumors with loss of expression of Z1 MMR protein more frequently had absent PTEN immunostaining, which is in agreement with previous reports in endometrial carcinomas. 36,37 PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. PTEN mutations more frequently occur in type I endometrial carcinomas (35-55%) compared with type II endometrial carcinomas (5-11%).…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…[38][39][40][41] Gain of function mutations in all three AKT genes have been identified in adult malignancies, including breast, colon, melanoma, and ovarian. [7,[42][43][44] No mutations have been identified in any AKT isoform in childhood cancer; however, chromosomal gains amplifying the AKT1 gene have been described recently in rare cases of childhood AML, T-cell ALL, and gliosarcoma. [45][46][47] Amplification of eIF4E, S6K1, and cyclin D have been reported in adult cancers, including breast and mantle cell lymphomas but not in pediatric tumors.…”

RhoA and RhoC -siRNA inhibit the proliferation and invasiveness activity of human gastric carcinoma by Rho/PI3K/Akt pathway

“…It is important to attempt to inhibit tumor growth in such a manner as to block the inhibition of the apoptotic signaling pathway in tumor cells [2][3][4] . RhoA is over expressed during tumorigenesis, and some reports showed that the overexpression of RhoA and RhoC is involved proliferation and invasion in gastric cancer [5,6] . The RhoA and RhoC proteins comprise an important s u b s e t o f t h e R h o G T Pa s e f a m i l y t h a t h a s b een implicated in invasive gastric carcinomas, and is related to the PI3K/Akt signal pathway.…”