Anglesio, M. S., Papadopoulos, N., Ayhan, A., Nazeran, T. M., Noë, M., Horlings, H. M., Lum, A., Jones, S., Senz, J., Seckin, T., Ho, J., Wu, R., Lac, V., Ogawa, H., Tessier-Cloutier, B., Alhassan, R., Wang, A., Wang, Y., Cohen, J. D., . . . Shih, I. (2017). Cancer-Associated Mutations in Endometriosis without Cancer. The New England journal of medicine, 376(19), 1835-1848. https://doi.org/10.1056/NEJMoa1614814
Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, et al. Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med. 2017;376(19):1835-1848. doi:10.1056/NEJMoa1614814
Anglesio, Michael S., et al. "Cancer-Associated Mutations in Endometriosis without Cancer." The New England journal of medicine, vol. 376, no. 19, 2017, pp. 1835-1848.
For EndNote, Zotero or Mendeley:
Open access
Free to read
No reuse license
Open Access
Free full text on PubMed Central (PMC5555376)
RRM Academy Synopsis
Deep endometriosis lesions can carry cancer-driver gene mutations
A 2017 laboratory sequencing study of deep endometriosis lesions from 39 women found that 10 of 39 lesions carried cancer driver gene mutations. No lesion contained cancer. Where the cell types could be separated, the mutations sat in gland-lining cells and were absent from stromal cells.
Key Findings
Whole-exome sequencing of 24 patients found somatic mutations in 19 (79%).
Five patients had mutations in genes that drive cancer: ARID1A, PIK3CA, KRAS, and PPP2R1A. The authors put the odds of that rate arising without selection at P=0.001 (binomial test).
Targeted sequencing found KRAS mutations in 2 of 3 patients, and droplet digital PCR in 3 of 12. Where cells were separated, mutations were in the epithelium, absent from the stroma.
One patient carried two different KRAS mutations. Another carried the identical KRAS mutation in three distinct lesions.
Across all 39 lesions, 10 (26%) carried driver mutations. Every mutation tested appeared to sit in the epithelial cells.
Interpretation
The study analyzed archived surgical tissue from 39 women with deep infiltrating endometriosis (mean age 37) at three centers. None had cancer or dysplasia. The study sampled tissue once, with no follow-up, so it cannot show who goes on to develop cancer. The authors cite a malignant transformation rate near 1%. They suggest that driver mutations alone do not suffice to drive transformation and do not indicate likely progression to cancer. Only a minority of patients had detectable driver mutations. Superficial and ovarian lesions were outside the study.
RRM Context
Restorative reproductive medicine asks what drives a woman's disease. The authors say current classification of endometriosis does not predict well how lesions behave. They note that hormonal therapy causes unacceptable side effects in many patients, and some do not respond, especially with deep disease. All samples came from removed tissue. Excision makes that tissue available for study.
Our editorial summary of this paper, not the article's abstract.
Abstract
Background
Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis.
Methods
We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations.
Results
Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions.
Conclusions
We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Rojas HE et al., 2026·Journal of women's health (2002)
To characterize differences between individuals with and without mid-cycle pain in a registry cohort with endometriosis. Prospective analysis of data from the Endometriosis Pelvic Pain Interdisciplinary Cohort Data Registry (Clinicaltrials.gov #NCT02911090) at a tertiary referral center in Western Canada. Three hundred forty-five individuals aged 18-49 years who: (1) had at least one episode of menstrual bleeding in the last 3 months, (2) attended a baseline initial visit, and (3) subsequently had surgery with histological confirmation of endometriosis between January 2018 and December 2023. Exclusion criteria included (1) previous hysterectomy; (2) hormonal suppressive therapy use in the last 3 months; and (3) missing data on mid-cycle pain, history of hormonal therapy use, or menstrual cycle regularity. N/A. Mid-cycle pain in the last month versus No mid-cycle pain in the last month. Of the 345 participants, 67% (n = 232) reported mid-cycle pain in the last month. Mid-cycle pain in the last month was significantly associated with higher mean Central Sensitization Inventory score (48 ± 17 versus 36 ± 16, p < 0.001) and more months of prior hormonal suppressive therapy use (58 [14-120] versus 26 [0-109], p = 0.012). Abnormal anatomy at the time of surgery (e.g., endometrioma, ovarian adhesions) was not associated with mid-cycle pain in the last month. In this endometriosis cohort at a tertiary referral center, most participants reported mid-cycle pain in the last month, which was associated with central sensitization but was not clearly related to endometriosis anatomical distortion.
Bouchard TP et al., 2026·Reproductive biomedicine online·Free to read
Do quantitative urinary hormone measurements on the Mira monitor predict and confirm ovulation accurately compared with ultrasound in women with regular menstrual cycles? Do Mira urine hormones correlate with serum hormones?
This was a prospective, single-centre, blinded diagnostic accuracy study with 52 women aged 19-44 years with regular cycles (24-38 days) who tracked 153 cycles over 18 months. Daily first-morning urine was tested with the Mira monitor for follicle stimulating hormone (FSH), oestrone-3-glucuronide (E13G), luteinizing hormone (LH) and pregnanediol glucuronide (PDG). Serial transvaginal ultrasounds (890 scans) confirmed the day of ovulation. Serum hormones were measured twice per cycle. The 121 ovulatory cycles from 49 participants with sufficient index test and reference standard data were included in the final analysis.
The Mira LH peak day strongly predicted ultrasound-confirmed ovulation (R² = 0.96, P < 0.001; intraclass correlation coefficient = 0.971), with 96% of ovulations occurring within ±1 day. The Mira PDG increase was also strongly associated with ultrasound-confirmed day of ovulation (R² = 0.87, P < 0.001). First-morning urine hormones were significantly associated with serum hormones when collected within 90 min (LH: R² = 0.92; E13G: R² = 0.73; R² = 0.61; R² = 0.75). Anovulatory cycles were identified in 11% of regularly cycling participants.
Quantitative urinary hormone monitoring with the Mira monitor provides accurate prediction and confirmation of ovulation, with strong urine-serum associations supporting reduced reliance on serial serum draws in select patients. These findings support clinical adoption of quantitative urinary fertility monitoring.
Balachandran S et al., 2026·Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC
To assess the impact of the COVID-19 pandemic on reproductive outcomes in patients with recurrent pregnancy loss (RPL) and the influence of material and social deprivation on these outcomes.
This retrospective cohort study included RPL patients seen at a specialized clinic between March 1, 2018, and February 28, 2022. Patients were categorized into two groups based on care period: pre-pandemic (March 1, 2018-February 29, 2020) and pandemic (March 1, 2020-February 28, 2022). Cumulative probabilities of birth were estimated using the cumulative incidence function within a competing risk framework, treating pregnancy loss as a competing event. Fine and Gray regression models calculated sub-distribution hazard ratio (sHR) of birth.
544 patients were included in the study, with 255 in the pre-pandemic group and 289 in the pandemic group. Individuals in the pandemic group were less likely to achieve pregnancy than those in the pre-pandemic group (relative risk = 0.50, 95% confidence interval [CI] 0.39 - 0.66). Among those who conceived, the cumulative probability of live birth was 0.77 in both groups. Relative to individuals residing in high-social deprivation neighborhoods, those living in moderately deprived areas had higher sub-distribution hazards of live birth (adjusted sHR = 1.97, 95% CI 1.25 - 3.10; P = 0.003).
Within specialized RPL care and a universal maternity care system, pregnancy rates were lower during the first two years of the COVID-19 pandemic. However, among those who conceived, the probability of achieving a live birth remained similar between the pre-pandemic and pandemic periods.
Bouchard TP et al., 2026·Reproductive biomedicine online·Free to read
Does formation of the corpus luteum help to identify the day of ovulation on ultrasound when follicular collapse is missed, and how reliable are sonographers versus a review panel in identifying the day of ovulation on ultrasound? Sonographers in a clinic in Canada performed serial endovaginal ultrasound scans (six to eight per cycle) to identify the day of ovulation in regularly cycling women (n = 40) who were followed for one to five cycles (n = 85). The day of ovulation was identified by: (i) identification of the dominant follicle; (ii) disappearance of the dominant follicle; and (iii) identification and dating of the corpus luteum. The main outcome measures were inter-rater reliability between two sonographers, and Bland-Altman agreement between the supervising sonographer and a panel that reviewed each scan to identify the day of ovulation. Of the 85 menstrual cycles reviewed, two cycles did not have sufficient data to date ovulation, one cycle showed an incidental dermoid cyst, and 11 cycles showed anovulatory patterns. This left a total of 71 cycles (84%) for which intra-rater reliability between two sonographers for identifying the day of ovulation was high (intraclass correlation coefficient = 0.99, P < 0.0001), and Bland-Altman agreement showed no significant difference in the estimated day of ovulation between the supervising sonographer and the panel (t = -0.28, P = 0.78). Corpus luteum criteria were necessary to help identify the day of ovulation in 14 of 71 cycles (20%). The estimated day of ovulation can be determined reliably on ultrasound by trained sonographers using collapse of the dominant follicle and formation of the corpus luteum based on six to eight scans per cycle.
Samartzis EP et al., 2020·Annals of translational medicine·Free full text on PubMed Central
Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.
Dawson A et al., 2018·Ecancermedicalscience·Free full text on PubMed Central
Endometriosis is a fascinating disease that we strive to better understand. Molecular techniques are shedding new light on many important aspects of this disease: from pathogenesis to the recognition of distinct disease variants like deep infiltrating endometriosis. The observation that endometriosis is a cancer precursor has now been strengthened with the knowledge that mutations that are present in endometriosis-associated cancers can be found in adjacent endometriosis lesions. Recent genomic studies, placed in context, suggest that deep infiltrating endometriosis may represent a benign neoplasm that invades locally but rarely metastasises. Further research will help elucidate distinct aberrations which result in this phenotype. With respect to identifying those patients who may be at risk of developing endometriosis-associated cancers, a combination of molecular, pathological, and inheritance markers may define a high-risk group that might benefit from risk-reducing strategies.
We analyzed 81 ovarian cancers for loss of heterozygosity (LOH) on 10q23 and for mutations in PTEN. LOH was common among the endometrioid (43%) and serous (28%) cancers, but was infrequent among the other histological subtypes. Somatic PTEN mutations were detected in seven (21%) endometrioid cancers and the mutation in all informative cases was accompanied by loss of the wild-type allele. One mucinous cancer without 10q23 LOH was shown to harbor two somatic PTEN mutations. Frequent LOH was observed on chromosome 6q (60.0%) and chromosome 10q (40.0%) in ovarian atypical endometriosis, but no PTEN mutations were observed. These findings support the hypothesis that endometrioid and clear cell ovarian carcinomas may arise through malignant transformation of endometriotic lesions.
Endometriosis is a common gynecological disease in which tissue similar to the endometrium proliferates at sites outside the uterine cavity. Malignant transformation of endometriosis to endometrioid and clear cell ovarian carcinomas has been documented in histological studies, but no molecular genetic evidence exists to support that endometriosis is the clonal precursor of such malignancies. We examined 14 cases of endometriosis synchronous with ovarian cancer for loss of heterozygosity on 12 chromosome arms, X chromosome inactivation, and TP53 mutation to determine whether they shared genetic alterations. In all four of the cases where the carcinoma had arisen within endometriosis and in five of the seven cases where the carcinoma was adjacent to the endometriosis, common genetic lesions were detected, consistent with a common lineage. A TP53 mutation was also detected in one case of endometriosis adjacent to carcinoma. These findings support the numerous histological observations that endometrioid and clear cell ovarian carcinomas may arise through malignant transformation of endometriotic lesions.
General Gynecology › Gynecologic Oncology › Ovarian Cancer · Endometriosis › Pathophysiology › Genetics
Michael S Anglesio, Nickolas Papadopoulos, Ayse Ayhan, Michaël Noë, Hugo M Horlings, Amy Lum, Siân Jones, Janine Senz, Tamer Seckin, Ren-Chin Wu, Vivian Lac, Hiroshi Ogawa, Yuanyuan Wang, Joshua D Cohen, Minming Zhang, Maria Popoli, Laura D Wood, Catherine Allaire, Cristian Tomasetti, Kenneth W Kinzler, Tian-Li Wang, Bert Vogelstein, Paul J Yong, David G Huntsman, Ie-Ming Shih, Rami Alhassan, Niki Boyd, Luis Diaz, C Blake Gilks, Adnan Hasanovic, Julie Ho, Wyatt McMahon, Tayyebeh M Nazeran, Amy Wang, Christina Williams, Fontayne Wong
Mike Anglesio, M Anglesio, N Papadopoulos, A Ayhan, M Noë, H Horlings, A Lum, S Jones, J Senz, T Seckin, R Wu, V Lac, H Ogawa, Y Wang, Josh Cohen, J Cohen, M Zhang, M Popoli, L Wood, Cathy Allaire, Kate Allaire, C Allaire, C Tomasetti, Ken Kinzler, K Kinzler, T Wang, B Vogelstein, P Yong, Dave Huntsman, D Huntsman, I Shih, R Alhassan, N Boyd, L Diaz, A Hasanovic, J Ho, W McMahon, T Nazeran, A Wang, C Williams, F Wong
PMID 28489996 28489996 DOI 10.1056/NEJMoa1614814 10.1056/NEJMoa1614814 Anglesio et al. 2017, Anglesio 2017
Cite this article
Anglesio, M. S., Papadopoulos, N., Ayhan, A., Nazeran, T. M., Noë, M., Horlings, H. M., Lum, A., Jones, S., Senz, J., Seckin, T., Ho, J., Wu, R., Lac, V., Ogawa, H., Tessier-Cloutier, B., Alhassan, R., Wang, A., Wang, Y., Cohen, J. D., . . . Shih, I. (2017). Cancer-Associated Mutations in Endometriosis without Cancer. The New England journal of medicine, 376(19), 1835-1848. https://doi.org/10.1056/NEJMoa1614814
Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, et al. Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med. 2017;376(19):1835-1848. doi:10.1056/NEJMoa1614814
Anglesio, Michael S., et al. "Cancer-Associated Mutations in Endometriosis without Cancer." The New England journal of medicine, vol. 376, no. 19, 2017, pp. 1835-1848.
Keywords
Adult, Cell Transformation, Neoplastic/genetics, Class I Phosphatidylinositol 3-Kinases, DNA Mutational Analysis/methods, DNA-Binding Proteins, Endometriosis/genetics/pathology, Endometrium/pathology, Exome, Female, Humans, Middle Aged, Mutation, Nuclear Proteins/genetics, Phosphatidylinositol 3-Kinases/genetics, Polymerase Chain Reaction, Protein Phosphatase 2/genetics, Proto-Oncogene Proteins P21(ras)/genetics, Transcription Factors/genetics, ARID1A Protein, Human, DNA-Binding Proteins, KRAS Protein, Human, Nuclear Proteins, PPP2R1A Protein, Human, Transcription Factors, Class I Phosphatidylinositol 3-Kinases, PIK3CA Protein, Human, Protein Phosphatase 2, Proto-Oncogene Proteins P21(ras)