Cancer-Associated Mutations in Endometriosis without Cancer

Michael S Anglesio; Nickolas Papadopoulos; Ayse Ayhan; Tayyebeh M Nazeran; Michaël Noë; Hugo M Horlings; Amy Lum; Siân Jones; Janine Senz; Tamer Seckin; Julie Ho; Ren-Chin Wu; Vivian Lac; Hiroshi Ogawa; Basile Tessier-Cloutier; Rami Alhassan; Amy Wang; Yuxuan Wang; Joshua D Cohen; Fontayne Wong; Adnan Hasanovic; Natasha Orr; Ming Zhang; Maria Popoli; Wyatt McMahon; Laura D Wood; Austin Mattox; Catherine Allaire; James Segars; Christina Williams; Cristian Tomasetti; Niki Boyd; Kenneth W Kinzler; C Blake Gilks; Luis Diaz; Tian-Li Wang; Bert Vogelstein; Paul J Yong; David G Huntsman; Ie-Ming Shih

doi:10.1056/NEJMoa1614814

Cancer-Associated Mutations in Endometriosis without Cancer

Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, Lum A, Jones S, Senz J, Seckin T, Ho J, Wu RC, Lac V, Ogawa H, Tessier-Cloutier B, Alhassan R, Wang A, Wang Y, Cohen JD, Wong F, Hasanovic A, Orr N, Zhang M, Popoli M, McMahon W, Wood LD, Mattox A, Allaire C, Segars J, Williams C, Tomasetti C, Boyd N, Kinzler KW, Gilks CB, Diaz L, Wang TL, Vogelstein B, Yong PJ, Huntsman DG, Shih IM

Published May 11, 2017 The New England Journal of Medicine, 376(19), 1835-1848

DOI 10.1056/NEJMoa1614814 PMID 28489996 PMC 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.

About 8 in 10 women with deep endometriosis had somatic mutations in their lesions. Source: Anglesio MS et al., 2017, PMID 28489996.

Study at a glance, laboratory sequencing study of 39 women: Deep endometriosis lesions can carry cancer-driver gene mutations. Source: Anglesio MS et al., 2017, PMID 28489996.

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

This laboratory sequencing study analyzed archived surgical tissue from 39 women with deep infiltrating endometriosis (mean age 37) at three centers. None of the women had cancer or dysplasia. The authors cite a malignant transformation rate near 1% for endometriosis overall. The authors note that driver mutations alone do not appear sufficient to drive malignant transformation. The findings support larger studies of cancer-driver mutations in endometriosis lesions.

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.

Read the guide

Endometriosis Explained: Diagnosis, Excision Surgery, and the RRM Approach

Endometriosis is a chronic inflammatory disease that drives pain, organ dysfunction, and infertility. How RRM-trained clinicians diagnose and treat it through excision surgery, cycle charting, and longitudinal care.

22 min read

Topics

General Gynecology › Gynecologic Oncology › Ovarian Cancer · Endometriosis › Pathophysiology › Genetics

Michael S Anglesio, Nickolas Papadopoulos, Ayse Ayhan, Tayyebeh M Nazeran, Michaël Noë, Hugo M Horlings, Amy Lum, Siân Jones, Janine Senz, Tamer Seckin, Julie Ho, Ren-Chin Wu, Vivian Lac, Hiroshi Ogawa, Basile Tessier-Cloutier, Rami Alhassan, Amy Wang, Yuxuan Wang, Joshua D Cohen, Fontayne Wong, Adnan Hasanovic, Natasha Orr, Ming Zhang, Maria Popoli, Wyatt McMahon, Laura D Wood, Austin Mattox, Catherine Allaire, James Segars, Christina Williams, Cristian Tomasetti, Niki Boyd, Kenneth W Kinzler, C Blake Gilks, Luis Diaz, Tian-Li Wang, Bert Vogelstein, Paul J Yong, David G Huntsman, Ie-Ming Shih

Mike Anglesio, M Anglesio, N Papadopoulos, A Ayhan, T Nazeran, M Noë, H Horlings, A Lum, S Jones, J Senz, T Seckin, J Ho, R Wu, V Lac, H Ogawa, B Tessier-Cloutier, R Alhassan, A Wang, Y Wang, Josh Cohen, J Cohen, F Wong, A Hasanovic, N Orr, M Zhang, M Popoli, W McMahon, L Wood, A Mattox, Cathy Allaire, Kate Allaire, C Allaire, Jim Segars, Jimmy Segars, J Segars, C Williams, C Tomasetti, N Boyd, Ken Kinzler, K Kinzler, L Diaz, T Wang, B Vogelstein, P Yong, Dave Huntsman, D Huntsman, I Shih

PMID 28489996 28489996 DOI 10.1056/NEJMoa1614814 10.1056/NEJMoa1614814 Anglesio et al. 2017, Anglesio 2017

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)

Cancer-Associated Mutations in Endometriosis without Cancer

Deep endometriosis lesions can carry cancer-driver gene mutations

Key Findings

Interpretation

RRM Context

Abstract

Read the guide

Topics

By this author

Related research

Keywords