Comments on: Gene Polymorphisms in FAS (Rs3740286 and Rs4064) are Involved in Endometriosis Development in Brazilian Women, but not those in CASP8 (rs13416436 and rs2037815)

We read with great interest the article by Pissetti et al[1] entitled ‘Gene Polymorphisms in FAS (Rs3740286 and Rs4064) Are Involved in Endometriosis Development in Brazilian Women, but not those in CASP8 (rs13416436 and rs2037815),’ published in your journal. The authors investigated the association between two polymorphisms involved in apoptosis and the risk of developing endometriosis in a case-control study enrolling 45 women. Interestingly, they found a positive association between polymorphisms of the Fas cell surface death receptor gene FAS and the confirmed surgical diagnosis of endometriosis.

The authors investigated polymorphisms of the FAS gene, similarly to other previous authors.[2] Overall, one of the alterations appearing in the eutopic and ectopic endometria of women with endometriosis refers to the regulation of apoptosis. In fact, anomalous susceptibility of endometrial tissue to apoptosis may deeply contribute to the development of implants[3]; in particular, it has been reported that expressions of FAS and its ligand may be decreased in eutopic and ectopic endometria of women with endometriosis.[4] In contrast, higher levels of proapoptotic proteins, such as FAS ligand, in the peritoneal fluid of women with endometriosis may contribute to an increased apoptosis of immune cells, leading to decreased scavenger activity in the peritoneal cavity and, thus, less immune clearance.[5]

Pissetti et al[1] should be congratulated for their laboratory findings regarding a controversial and complex topic. In any case, we would be glad to make some considerations on this interesting study. First, it would be of particular interest to know if the presence of these polymorphisms would be different in patients with implants originating from peritoneal nodules, ovarian endometriomas or deep infiltrating endometriosis, three distinguished phenotypes of endometriosis that are known to have probably different pathogeneses.[6] In relation to this, it has been previously supposed that apoptosis could especially contribute to the survival of endometrial cells regurgitated in the peritoneal cavity and the subsequent development of peritoneal endometriotic implants.[3]

Although the authors correctly reported the distribution of the different endometriosis stages in the patients' population, according to the American Society for Reproductive Medicine (ASRM) classification, it would be interesting to know if there has been a specific correlation between FAS genetic polymorphisms and a higher median endometriosis stage or a worse patients' clinical symptomatology.

In conclusion, the role of apoptosis in endometriosis appears to be an attractive topic; in the near future, this pathway may represent a suitable target for treatment of this disease, which needs a chronic therapy balancing clinical efficacy with tolerability.[7] In support of this view, in a recent narrative review, we found preclinical experiments in vitro and in animal models focalized on drugs acting on apoptosis.[8] Furthermore, as stated by the authors, the investigation of these polymorphisms as biomarkers to determine predisposition and prognosis for endometriosis appears another fascinating opportunity.

• References

• 1 Pissetti CW, Tanaka SCSV, Hortolani ACC, Marqui ABT. Gene polymorphisms in FAS (Rs3740286 and Rs4064) are involved in endometriosis development in Brazilian women, but not those in CASP8 (rs13416436 and rs2037815). Rev Bras Ginecol Obstet 2018; 40 (08) 450-457 Doi: 10.1055/s-0038-1667183
• 2 Fernández RM, Noval JA, García-Lozano JC, Borrego S, Moliní JL, Antiñolo G. Polymorphisms in the promoter regions of FAS and FASL genes as candidate genetic factors conferring susceptibility to endometriosis. Int J Mol Med 2005; 15 (05) 865-869 Doi: 10.3892/ijmm.15.5.865
• 3 Taniguchi F, Kaponis A, Izawa M. , et al. Apoptosis and endometriosis. Front Biosci (Elite Ed) 2011; 3: 648-662
• 4 Sbracia M, Valeri C, Antonini G, Biagiotti G, Pacchiarotti A, Pacchiarotti A. Fas and Fas-Ligand in eutopic and ectopic endometrium of women with endometriosis: the possible immune privilege of ectopic endometrium. Reprod Sci 2016; 23 (01) 81-86 Doi: 10.1177/1933719115594019
• 5 Garcia-Velasco JA, Mulayim N, Kayisli UA, Arici A. Elevated soluble Fas ligand levels may suggest a role for apoptosis in women with endometriosis. Fertil Steril 2002; 78 (04) 855-859 Doi: 10.1016/S0015-0282(02)03320-4
• 6 Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014; 10 (05) 261-275 Doi: 10.1038/nrendo.2013.255
• 7 Ferrero S, Evangelisti G, Barra F. Current and emerging treatment options for endometriosis. Expert Opin Pharmacother 2018; 19 (10) 1109-1125 Doi: 10.1080/14656566.2018.1494154
• 8 Barra F, Scala C, Mais V, Guerriero S, Ferrero S. Investigational drugs for the treatment of endometriosis, an update on recent developments. Expert Opin Investig Drugs 2018; 27 (05) 445-458 Doi: 10.1080/13543784.2018.1471135
• 9 Pissetti CW, Tanaka SCSV, Hortolani ACC, Marqui ABT. Gene polymorphisms in FAS (Rs3740286 and Rs4064) are involved in endometriosis development in Brazilian women, but not those in CASP8 (rs13416436 and rs2037815). Rev Bras Ginecol Obstet 2018; 40 (08) 450-457 Doi: 10.1055/s-0038-1667183
• 10 Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997; 68 (04) 585-596 Doi: 10.1016/S0015-0282(97)00191-X
• 11 Liu X, Zhang Q, Guo SW. Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis. Reprod Sci 2018; 25 (03) 329-340 Doi: 10.1177/1933719117718275
• 12 Podgaec S. Manual de Endometriose: 2014/2015. São Paulo, SP: Federação Brasileira das Associações de Ginecologia e Obstetrícia; 2014
• 13 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67 (05) 817-821 Doi: 10.1016/S0015-0282(97)81391-X