Cancer‐associated mutations in normal human endometrium: Surprise or expected?

Kyo, Satoru; Sato, Seiya; Nakayama, Kentaro

doi:10.1111/cas.14571

Cited by 23 publications

(22 citation statements)

References 46 publications

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“…Several studies, including by our group, have recently reported that representative oncogenes of human cancers, such as KRAS and PIK3CA , are frequently mutated in ovarian endometriosis, 12 deep infiltrating endometriosis, 13 and iatrogenic endometriosis 14 . Moreover, those oncogenes have also been identified in normal endometrium 12,15‐18 . In our study, KRAS was most frequently mutated in ovarian endometriosis, with 23/54 (42.6%) of endometriosis cases harboring somatic KRAS mutations 12 .…”

Section: Introductionsupporting

confidence: 62%

Biological significance of KRAS mutant allele expression in ovarian endometriosis

et al. 2021

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KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation‐specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin‐fixed paraffin‐embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild‐type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild‐type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild‐type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.

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Section: Introductionsupporting

confidence: 62%

Biological significance of KRAS mutant allele expression in ovarian endometriosis

et al. 2021

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“…Considering that isolated driver mutations of ARID1A or PIK3CA transduced into normal endometrial epithelium have no gross phenotypes, but in combination, the atypical phenotype arises [ 30 ], a similar requirement may apply to expose the phenotype of KRAS mutation in the endometrial epithelium. Moreover, in normal endometrium and in ovarian endometrioma, similar driver mutations are found; however, the mutant allele frequency is higher in the latter [ 17 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

Koppolu

Maksym

Paskal

et al. 2021

Cells

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Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

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“…Furthermore, the process of epithelial-to-mesenchymal transition (EMT) seems to be crucial in the development of adenomyosis but also plays an important role in carcinogenesis [ 31 , 32 ]. Several studies have shown that changes in genes like AT-rich interactive domain-containing protein 1A (ARID1A), PTEN, KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) are present in women with endometriosis, but these are also known cancer-driving mutations involved in endometrial cancer carcinogenesis [ 33 , 34 ]. However, cancer-associated mutations were also found in endometriotic lesions without concurrent cancer, in particular in deep infiltrating lesions which are rarely associated with cancer development [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Endometrial Cancer Incidence in Endometriosis and Adenomyosis

Hermens

Altena

Velthuis

et al. 2021

Cancers

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Women with histologically proven endometriosis/adenomyosis have an increased risk of ovarian cancer. Small studies show conflicting results on the endometrial cancer risk in women with endometriosis/adenomyosis. Therefore, we assessed the incidence of endometrial cancer in women with histologically proven endometriosis or adenomyosis. We performed a population-based retrospective cohort study of 129,862 women with histologically proven endometriosis/adenomyosis, matched with 132,700 women with a nevus selected from the Dutch pathology registry between 1990 and 2015. Histology results for endometrial cancer were retrieved. Crude and age-adjusted odds ratios for endometrial cancer were estimated. In the endometriosis/adenomyosis group, 1827 (1.4%) women had a histological report on endometrial cancer, and in the nevus group, 771 (0.6%) women. The age-adjusted OR for endometrial cancer was 2.58 (95%CI 2.37–2.81). After excluding the first year of follow-up, the age-adjusted OR was 0.76 (95%CI 0.63–0.92), indicating that endometrial cancer is most often found at time of histological diagnosis of endometriosis/adenomyosis. In around 20% of the endometrial cancer cases, the endometrial cancer was not recognized until after hysterectomy. Of these women, 35% had no prior (micro)curettage or biopsy. This study shows an increased incidence of endometrial cancer in women with histologically proven endometriosis and adenomyosis.

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Cancer‐associated mutations in normal human endometrium: Surprise or expected?

Cited by 23 publications

References 46 publications

Biological significance of KRAS mutant allele expression in ovarian endometriosis

Biological significance of KRAS mutant allele expression in ovarian endometriosis

Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

Endometrial Cancer Incidence in Endometriosis and Adenomyosis

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