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

• Published in: International journal of cancer Vol. 119; no. 3; pp. 563 - 570
• Main Authors: Bilbao, Cristina, Rodríguez, Germán, Ramírez, Raquel, Falcón, Orlando, León, Laureano, Chirino, Ricardo, Rivero, Juan F., Díaz‐Chico, B. Nicolás, Díaz‐Chico, Juan C., Perucho, Manuel
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2006; Wiley-Liss
• Subjects: Aged; Biological and medical sciences; endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Female; Female genital diseases; Gene Frequency; Genotype; Gynecology. Andrology. Obstetrics; Humans; Loss of Heterozygosity; Medical sciences; microsatellite instability; Microsatellite Repeats - genetics; Middle Aged; Mutation; Neoplasm Staging; PTEN mutation; PTEN Phosphohydrolase - genetics; Survival Analysis; Tumors; Human; microsatellite instability; Endometrium cancer; Malignant tumor; Carcinogenesis; Female genital diseases; Cancerology; Microsatellite DNA; Uterine diseases; endometrial cancer; Genetics; Instability; PTEN Gene; Mutation; PTEN mutation; Tumor suppressor gene
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.21862

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. © 2006 Wiley‐Liss, Inc.