Background: Rett syndrome is caused by mutations in the X-linked gene MECP2. While MECP2 has been implicated in breast, colon, and prostate cancers, studies have reported that individuals with Rett syndrome have a low risk of cancer. Due to this, there is a need to investigate the molecular mechanism that contributes to the inverse relationship between Rett syndrome and cancers. This study therefore aims to use a systematic computational approach to identify genes within Rett syndrome which may be protective against breast, ovarian, and cervical cancers. This finding could have clinical implications for developing targeted therapies or diagnostic markers for these cancers.

Method: Publicly available transcriptomics data on Rett syndrome were analyzed with GEOR2.Venny 2.0, which was used to identify overlapping genes between Rett syndrome and breast, cervical, and ovarian cancers. We further analyzed their expression pattern using GEPIA2. ShinyGo and KM Plotter were used to perform functional analysis and survival analysis, respectively.

Results: A total of 250 overlapping genes were identified between Rett syndrome and breast, cervical, and ovarian cancers. NTRK3, EphA3, TFPI2, and WWC1 were upregulated in Rett syndrome but were significantly downregulated in the cancers, suggesting they may act as tumor suppressors. NTRK3, EphA3, TFPI2, and WWC1 significantly increased the survival probability of breast cancer cohorts, but they did not have the same effect on the other cancers. However, functional analysis revealed these genes may play a role in tumor suppression.

Conclusion: The NTRK3, EphA3, TFPI2, and WWC1 genes, which are upregulated in Rett syndrome but downregulated in breast, ovarian, and cervical cancers, may play a role in their inverse relationship.