New Susceptibility Loci for Endometriosis

In the Spotlight New Susceptibility Loci for Endometriosis Maria Rosa Maduro, PhD Endometriosis is an estrogen-dependent inflammatory disease that is believed to affect 5 % to 10% of women of childbearing age. It can be a painful, debilitating disease that commonly leads to infertility. The etiology(ies) of the disease has(ve) been hard to deter- mine. Therefore, efficient treatment and, certainly, prophylaxis have not been successfully achieved. Since endometriosis is characterized by the presence of endometrium-like tissue outside of the uterine cavity, it has been hypothesized that fragments of menstrual endometrium pass backward through the fallopian tubes to implant on perito- neal surfaces. This theory has, however, not been well received by all the experts in the field. However, the involvement of a genetic factor to the disease has been generally well accepted and supported by hereditary studies. Studies on genetic variants on/around candidate genes have failed to show strong associations with endometriosis. There- fore, to identify genes associated with endometriosis Uno et al have performed the first genome-wide association study for this disease and their results have recently been published in Nature Genetics (Nat. Genet, advance online publication, 1-4). Using 1907 samples from Japanese individuals with endome- triosis and 5292 controls, Uno and colleagues have been able to identify a locus with significant association to endometriosis located on chromosome 9 at a region including the cyclin- dependent kinase inhibitor 2B antisense RNA, CDKN2BAS. Fine single nucleotide polymorphisms (SNPs) mapping showed that the strongest association was located in intron 16 of this gene, which is known to be expressed in the uterus and to be implicated in the expression regulation of the tumor suppressor genes p15, p16,a n d p14. The authors believe that the silencing of these tumor suppressor genes by CDKN2BAS might have a prominent role in the development of endometriosis. In addition, Uno et al verified that a particular SNP, rs16826658, located in the LD block that includes WNT4 (wingless-type MMTV integration site family, member 4) on chromosome 1, presented a possible association with endome- triosis and may therefore be a candidate locus for endometrio- sis susceptibility. WNT4 is known to play a major role in the development of the female genital tract and to be expressed in the normal peritoneum. Thus, the authors hypothesize that endometriosis may arise through metaplasia using develop- mental pathways involved in the female genital tract. In sum, the work presented by Uno et al certainly adds to the better understanding of endometriosis, providing insights into its pathology and raising hopes for new and more efficient treatments. A Prophylactic Approach Against Breast Cancer Jaini et al have recently published on Nature Medicine (Nat. Med, 16(7), 799-803) a report on an autoimmune-mediated strategy for breast cancer prevention involving vaccination that may well revolutionize the way we look at this terrible disease. Up to now, cancer vaccine research has mostly focused on the therapy against already established tumors, as the develop- ment of prophylactic vaccines have been impaired by the diffi- culty of finding a tumor antigen that would not elicit profound autoimmune complications when used on a preventive vaccine setting. Jaini and colleagues seem to have successfully overcome this problem in mouse, where they generated a breast- specific a-lactalbumin antigen from lactating mammary tissue that was later used for immunization. Since this mammary- specific differentiation protein is highly expressed in breast carcinomas, the observed immunoreactivity provided substan- tial protection and therapy against breast tumor growth in both transgenic mouse models of breast cancer and transplanted breast tumors. In addition, because a-lactalbumin is only expressed in normal mammary epithelial cells during lactation, the vaccination-induced prophylaxis was carried out without any detectable inflammatory reaction of normal nonlactating tissue. Given the fact that several independent reports have con- firmed that a-lactalbumin is expressed in the majority of human breast malignancies at levels sufficient for detection by immunocytochemical analysis, the authors speculate that a-lactalbumin vaccination may provide a safe and effective protection against breast cancer in postchildbearing women. In sum, the data presented by Jaini et al provides experimen- tal support for the potential development of reliable and safe protection, not only against breast cancer but also against other tumor types, by the targeted vaccination against tissue-specific and conditionally expressed protein antigens. Reproductive Sciences 17(10) 885 ª The Author(s) 2010 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719110383671 http://rs.sagepub.com