Patterns of Loss of Heterozygosity at 10q23.3 and Microsatellite Instability in Endometriosis, Atypical Endometriosis, and Ovarian Carcinoma Arising in Association With Endometriosis

Abstract

Genetic aberrations, such as loss of heterozygosity (LOH) and mutations leading to functional inactivation of the PTEN tumor suppressor gene, located on chromosome 10q23.3, have been shown to be associated with approximately one third of ovarian adenocarcinomas. In addition, microsatellite instability (MSI) leading to the functional inactivation of the PTEN gene has also been reported for ovarian adenocarcinomas with frequencies varying from 6 to 37%. However, the frequency of PTEN gene abnormalities has not been well studied or evaluated in lesions such as typical and atypical endometriosis. The aim of this study was to investigate a possible sequential progression from endometriosis through atypical endometriosis to ovarian carcinoma by assessing LOH at 10q23.3 and MSI in those entities. Genomic DNA was analyzed for LOH and MSI at 3 loci on chromosome 10, using polymerase chain reaction amplification. Significant differences in LOH were seen between endometriosis (4.3%) and ovarian carcinoma (23.5%) at D10S608. The differences at the other 2 loci were not significant. A high frequency of MSI was found in endometriosis (82.6%) and atypical endometriosis (75%); however, the differences were not significant. These results suggest that LOH at D105608 may possibly be an important molecular event in the progression of endometriosis to carcinoma. This study highlights that endometriosis and atypical endometriosis might act as precursor lesions that have the potential to progress into ovarian adenocarcinoma.

Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (Review)

“…For example, hyperplastic polyps in colon are part of the distinct pathway of colorectal carcinogenesis characterized by MSI and deficiency in DNA MMR. Although the relationship between endometriosis and MSI has been controversial (6), a high frequency (~80%) of MSI was found in endometriosis and atypical endometriosis (14,25). In addition, methylation phenotype of hMLH1 gene (whose gene product is a component of the DNA MMR pathway) is correlated with microsatellite phenotype of MMR genes.…”

“…Hypermethylation of hMLH1 is noted in ~10% of endometriosis (17). The high-level MSI or MSI leading to the PTEN dysfunction has also been reported for EOC with frequencies varying from 6 to 37% (14,25,35). Low-grade EAC are predominantly characterized by MSI.…”

“…Genetic aberrations, such as LOH and somatic mutations leading to functional inactivation of the PTEN tumor suppressor gene, located on chromosome 10q23.3, have been identified in endometriosis (20%) (12,16) and one third of EOC (25). the frequency of LOH at 10q23.3 and PTEN somatic mutations in CCC and EAC was still higher than in other histological types of EOC, although LOH occurred less frequently in CCC (8%) than in EAC (20%) (16,26,27).…”

Endometriosis research using capture microdissection techniques: Progress and future applications

“…The PTEN gene encodes phosphatase, which inhibits apoptosis mediated by protein kinase B and participates in cellular signal transduction, leading to enhanced cell proliferation and survival. Sato et al (26) and Ali-Fehmi et al (31) detected LOH at 10q23.3 in 56.5 and 29% of endometriosis cases, respectively. In these studies, three specific loci on chromosome 10 were identified to exhibit the highest frequencies of LOH, leading to inactivation of the PTEN gene.…”

“…Although LOH has been extensively investigated in ovarian cancer, this phenomenon has been rarely studied and is inconsistent in solitary endometriosis (17,(26)(27)(28)(29)(30)(31)(32)(33) (Table II). LOH at locus 10q23.3 is associated with phosphatase and tensin homolog (PTEN), which is one of the most studied TSGs (26,(30)(31)(32)(33)(34). The PTEN gene encodes phosphatase, which inhibits apoptosis mediated by protein kinase B and participates in cellular signal transduction, leading to enhanced cell proliferation and survival.…”