First Genetic Marker of Endometriosis Risk Identified

NEW YORK – Almost one-third of 132 women with endometriosis had a genetic mutation affecting expression of the KRAS gene, compared with only 5.8% of the general population, according to Dr. Hugh S. Taylor, who presented the findings at the annual congress of the Endometriosis Foundation of America.

"This is the only clearly identified genetic cause of endometriosis," explained Dr. Taylor. The KRAS oncogene produces a protein involved primarily in regulating cell division. The defect found in the women with endometriosis has been localized to a regulatory region of the KRAS gene: the let-7 microRNA (miRNA) binding site in the 3’-untranslated region (UTR).

A high proliferation and invasion rate was seen in endometrial cells from women with the variant allele. These properties may facilitate the invasion of endometrial cells into peritoneum and ovarian cortex.

"This mechanism supports the most accepted theory for the origin of endometriosis – retrograde menstruation and subsequent implantation and invasion of susceptible tissues ... The fact that only a portion of women develop this disease despite the nearly universal occurrence of retrograde menstruation could be explained by the presence of this allele," said Dr. Taylor, director of the division of reproductive endocrinology and infertility at Yale University, New Haven, Conn. The findings were published in the March issue of EMBO Molecular Medicine (EMBO Mol. Med. 2012;4:206-17) (Olga Grechukhina is the first author).

Since the mutation occurs only in a subgroup of women with endometriosis, genetic testing cannot be used as a screening tool. However, the recognition of KRAS-related endometriosis may allow for screening of family members and may have value for personalizing treatment of endometriosis, said Dr. Taylor.

Several lines of evidence reported by Dr. Taylor pinpoint the importance of this genetic mutation. In addition to the clinical observation that 31% of the sample of 132 women with endometriosis had this polymorphism compared with 5.8% of the control population, KRAS mRNA and protein levels were significantly increased in cultured endometrial stromal cells of women with the KRAS variant.

Dr. Taylor also looked at the behavior of endometrial stromal cells from women with and without the variant. Compared with cells from women without endometriosis, cells from women with endometriosis but without the variant were more invasive and proliferative. But cells from women with endometriosis and the variant had even higher levels of invasiveness and proliferation.

In another experiment, cells taken from women with endometriosis were transplanted under the kidney capsules of immunodeficient mice. Cells from the women with the mutation proliferated faster and had a lower expression of the progesterone receptor. "Progesterone resistance is characteristic of some women with endometriosis," commented Dr. Taylor.

Women with the mutation have a much lower expression of all let-7 miRNAs, not just let-7a. "Let-7 doesn’t just bind KRAS – it binds and generally downregulates many genes. When let-7 is inhibited, it no longer stops the expression of many genes involved in mitotic signaling, cell cycling and cell adhesion and migration," explained Dr. Taylor.

Dr. Taylor had no relevant financial disclosures.

NEW YORK – Almost one-third of 132 women with endometriosis had a genetic mutation affecting expression of the KRAS gene, compared with only 5.8% of the general population, according to Dr. Hugh S. Taylor, who presented the findings at the annual congress of the Endometriosis Foundation of America.

"This is the only clearly identified genetic cause of endometriosis," explained Dr. Taylor. The KRAS oncogene produces a protein involved primarily in regulating cell division. The defect found in the women with endometriosis has been localized to a regulatory region of the KRAS gene: the let-7 microRNA (miRNA) binding site in the 3’-untranslated region (UTR).

A high proliferation and invasion rate was seen in endometrial cells from women with the variant allele. These properties may facilitate the invasion of endometrial cells into peritoneum and ovarian cortex.

"This mechanism supports the most accepted theory for the origin of endometriosis – retrograde menstruation and subsequent implantation and invasion of susceptible tissues ... The fact that only a portion of women develop this disease despite the nearly universal occurrence of retrograde menstruation could be explained by the presence of this allele," said Dr. Taylor, director of the division of reproductive endocrinology and infertility at Yale University, New Haven, Conn. The findings were published in the March issue of EMBO Molecular Medicine (EMBO Mol. Med. 2012;4:206-17) (Olga Grechukhina is the first author).

Since the mutation occurs only in a subgroup of women with endometriosis, genetic testing cannot be used as a screening tool. However, the recognition of KRAS-related endometriosis may allow for screening of family members and may have value for personalizing treatment of endometriosis, said Dr. Taylor.

Several lines of evidence reported by Dr. Taylor pinpoint the importance of this genetic mutation. In addition to the clinical observation that 31% of the sample of 132 women with endometriosis had this polymorphism compared with 5.8% of the control population, KRAS mRNA and protein levels were significantly increased in cultured endometrial stromal cells of women with the KRAS variant.

Dr. Taylor also looked at the behavior of endometrial stromal cells from women with and without the variant. Compared with cells from women without endometriosis, cells from women with endometriosis but without the variant were more invasive and proliferative. But cells from women with endometriosis and the variant had even higher levels of invasiveness and proliferation.

In another experiment, cells taken from women with endometriosis were transplanted under the kidney capsules of immunodeficient mice. Cells from the women with the mutation proliferated faster and had a lower expression of the progesterone receptor. "Progesterone resistance is characteristic of some women with endometriosis," commented Dr. Taylor.

Women with the mutation have a much lower expression of all let-7 miRNAs, not just let-7a. "Let-7 doesn’t just bind KRAS – it binds and generally downregulates many genes. When let-7 is inhibited, it no longer stops the expression of many genes involved in mitotic signaling, cell cycling and cell adhesion and migration," explained Dr. Taylor.

Dr. Taylor had no relevant financial disclosures.

NEW YORK – Almost one-third of 132 women with endometriosis had a genetic mutation affecting expression of the KRAS gene, compared with only 5.8% of the general population, according to Dr. Hugh S. Taylor, who presented the findings at the annual congress of the Endometriosis Foundation of America.

"This is the only clearly identified genetic cause of endometriosis," explained Dr. Taylor. The KRAS oncogene produces a protein involved primarily in regulating cell division. The defect found in the women with endometriosis has been localized to a regulatory region of the KRAS gene: the let-7 microRNA (miRNA) binding site in the 3’-untranslated region (UTR).

A high proliferation and invasion rate was seen in endometrial cells from women with the variant allele. These properties may facilitate the invasion of endometrial cells into peritoneum and ovarian cortex.

"This mechanism supports the most accepted theory for the origin of endometriosis – retrograde menstruation and subsequent implantation and invasion of susceptible tissues ... The fact that only a portion of women develop this disease despite the nearly universal occurrence of retrograde menstruation could be explained by the presence of this allele," said Dr. Taylor, director of the division of reproductive endocrinology and infertility at Yale University, New Haven, Conn. The findings were published in the March issue of EMBO Molecular Medicine (EMBO Mol. Med. 2012;4:206-17) (Olga Grechukhina is the first author).

Since the mutation occurs only in a subgroup of women with endometriosis, genetic testing cannot be used as a screening tool. However, the recognition of KRAS-related endometriosis may allow for screening of family members and may have value for personalizing treatment of endometriosis, said Dr. Taylor.

Several lines of evidence reported by Dr. Taylor pinpoint the importance of this genetic mutation. In addition to the clinical observation that 31% of the sample of 132 women with endometriosis had this polymorphism compared with 5.8% of the control population, KRAS mRNA and protein levels were significantly increased in cultured endometrial stromal cells of women with the KRAS variant.

Dr. Taylor also looked at the behavior of endometrial stromal cells from women with and without the variant. Compared with cells from women without endometriosis, cells from women with endometriosis but without the variant were more invasive and proliferative. But cells from women with endometriosis and the variant had even higher levels of invasiveness and proliferation.

In another experiment, cells taken from women with endometriosis were transplanted under the kidney capsules of immunodeficient mice. Cells from the women with the mutation proliferated faster and had a lower expression of the progesterone receptor. "Progesterone resistance is characteristic of some women with endometriosis," commented Dr. Taylor.

Women with the mutation have a much lower expression of all let-7 miRNAs, not just let-7a. "Let-7 doesn’t just bind KRAS – it binds and generally downregulates many genes. When let-7 is inhibited, it no longer stops the expression of many genes involved in mitotic signaling, cell cycling and cell adhesion and migration," explained Dr. Taylor.

Dr. Taylor had no relevant financial disclosures.