DNA repair defects and Endometriosis

Genetic variants in the nucleotide excision repair genes are associated with the risk of developing endometriosis

Key Points

Highlight:

• Dr. Bau group from Taiwan suggest that genetic variations in the nucleotide excision repair genes may contribute to the endometriosis development.
• Genetic variations in some nucleotide excision repair genes seem to be highly associated with increased endometriosis development.

Background:

• Well-known characteristics in cancer such as genomic instability, the increased mutation rate in oncogenes, microsatellite instability, tissue-specific gene copy number changes, and lower expression of DNA repair enzymes are highly implicated in endometriosis research.
• Many studies support that lack of DNA repair is an important step for endometriosis development.
• SNPs of DNA repair genes in endometriosis, a well-known predisposing condition for some cancers, have not been studied yet.

Key points:

• A total of 153 patients with endometriosis and 636 healthy controls without endometriosis have participated.
• To search the variation of NER genes, 10 SNPs in six key NER pathway genes specifically focused on.
• Multivariate logistic regression analysis revealed that certain SNPs of NER genes, namely ERCC1 rs11615 TT, ERCC2 rs1799793 AA, ERCC6 rs2228528 AA genotype, were found significantly associated with endometriosis development, compared to the control.

Limitations:

• More investigations are required on the relationship between DNA repair and hormone regulation in the context of endometriosis development.
• Additional risk factors (more than smoking, alcohol consumption) and SNPs in other DNA repair genes in larger populations are highly required for better understanding.

Lay Summary

Endometriosis is a hormone-dependent disorder and highly associated with inflammation. It is well suggested that endometriosis increases the risks of developing cancers such as ovarian, breast, endocrine, and colorectal cancers. Compared to cancer, there are many similarities in endometriosis. Well-known characteristics in cancer such as genomic instability, the increased mutation rate in oncogenes, microsatellite instability, tissue-specific gene copy number changes, and lower expression of DNA repair enzymes are highly implicated in endometriosis.

DNA repair deficiency got lots of attention in endometriosis. Many studies support that lack of DNA repair is an important step for endometriosis development. First, the expression of mismatch repair proteins was decreased in a stepwise manner in progression from endometriosis to endometriosis-related ovarian carcinoma. This finding suggests that mismatch repair deficiency supports the malignant transformation of endometriosis. Second, the increased level of oxidative adduct 8-OHdG which suggests the defect of base excision repair was found in endometriosis. This defect was also shown in a stepwise manner of endometriosis progression. Impaired DNA double-strand break repair pathway was shown in patients with endometriosis. Furthermore, according to epidemiological studies, polymorphic variants in the DNA repair genes were associated with endometriosis. 

Maintaining DNA stability is the most fundamental issue in living organisms. Therefore, diverse DNA repair systems were developed to keep DNA integrity such as nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). According to the previous studies, single nucleotide polymorphisms (SNPs) in several NER genes are associated with diverse types of cancer development. However, it has not been studied their relationship with endometriosis, a well-known predisposing condition for some cancers.

To understand if the variation of NER genes could increase the development of endometriosis, Dr. Bau group evaluated the generic variations in critical NER genes in endometriosis. This study recently published in the journal of “Biology of Reproduction”.

For this study, a total of 153 patients with endometriosis and the 636 healthy controls without endometriosis have participated. To search the variation of NER genes, they specifically focus on 10 SNPs in six key NER pathway genes. From the multivariate logistic regression analysis, certain SNPs of NER genes, namely ERCC1 rs11615 TT, ERCC2 rs1799793 AA, ERCC6 rs2228528 AA genotype, are found to be significantly associated with endometriosis development compared to the control.

The authors believe that further studies are needed to investigate the relationship between DNA repair and hormone regulation in the context of endometriosis development. Also, additional risk factors (more than smoking, alcohol consumption) and SNPs in other DNA repair genes in larger populations are highly required for better understanding.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/?term=31373346