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Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.
This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.
All three subtypes of endometriosis exhibit “benign clinical behavior and normal-appearing histologic features,” and are considered to be nonmalignant inflammatory lesions, Dr. Anglesio and his associates said. However, they also “recapitulate some features of malignant neoplasms, including local invasion and resistance to apoptosis,” the investigators noted.
To further explore whether deep infiltrating endometriosis lesions harbor somatic mutations, they performed a series of genetic analyses on samples obtained from three independent cohorts of 27 affected patients in New York, Japan, and Vancouver. Whole-exome sequencing of lesions and adjacent normal tissue from 24 women revealed 80 different somatic mutations in 19 (79%) of the lesions.
The number of mutations per lesion varied widely, from 0 to 17, with a mean of 3.3 mutations per lesion. Five of these lesions harbored mutations in the cancer-driver genes ARID1A, PIK3CA, KRAS, or PPP2R1A.
In targeted-sequencing analyses of samples from three more patients, more activating mutations in the KRAS gene were found in two (66%). One woman had two different activating KRAS mutations, and the other had the same KRAS mutation in three separate lesions.
A further analysis of samples from an additional 12 patients showed KRAS mutations in 3 (25%) of them.
The data indicate that these mutations were very unlikely to have arisen by chance alone. In addition, “because cancer-driver mutations were present only in the epithelium but not the stroma of the same endometriosis lesion, we can assume that the observed mutations provide some key selective advantage to endometriotic epithelial cells,” Dr. Anglesio and his associates said (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMoa1614814).
Their findings are consistent with those of recent studies of other organ systems, which reported cancer-driver mutations in benign lesions and in normal tissues from skin, neuronal, and ovarian samples, they added.
“Our findings challenge the current understanding of this invasive subtype of endometriosis and open the discussion on whether deep infiltrating endometriosis can be considered as a benign neoplasm,” the investigators wrote.
This study was sponsored by 27 nonindustry sources, including the Johns Hopkins University, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ephraim and Wilma Shaw Roseman Foundation, the Endometriosis Foundation of America, and the National Institutes of Health. Dr. Anglesio reported having no relevant financial disclosures; some of his associates reported ties to several industry sources.
The variable patterns of somatic mutations discovered by Anglesio et al. are “intriguing” and raise many questions.
Do specific mutations in deep infiltrating endometriosis lesions contribute to the severity and progression of the disorder? Are such mutations to be found in other types of lesions? In endometrial precursor cells? Do specific mutations account for different presentations in different patients?
Exploring these questions will not be straightforward because of the difficulties in obtaining sufficient endometriotic tissue for genetic studies. Not only is it hard to get samples from peritoneal lesions, but the mutations occur in only one cell type – epithelium – which is even harder to isolate from mixed tissue samples.
Grant W. Montgomery, PhD, is at the Institute for Molecular Bioscience at the University of Queensland, Brisbane, Australia, and reported having no relevant financial disclosures. Linda C. Giudice, MD, PhD, is in the department of ob.gyn. and reproductive sciences at the University of California, San Francisco, and reported ties to AbbVie and Bayer. Dr. Montgomery and Dr. Giudice made these remarks in an editorial accompanying Dr. Anglesio’s report (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMe1701700).
The variable patterns of somatic mutations discovered by Anglesio et al. are “intriguing” and raise many questions.
Do specific mutations in deep infiltrating endometriosis lesions contribute to the severity and progression of the disorder? Are such mutations to be found in other types of lesions? In endometrial precursor cells? Do specific mutations account for different presentations in different patients?
Exploring these questions will not be straightforward because of the difficulties in obtaining sufficient endometriotic tissue for genetic studies. Not only is it hard to get samples from peritoneal lesions, but the mutations occur in only one cell type – epithelium – which is even harder to isolate from mixed tissue samples.
Grant W. Montgomery, PhD, is at the Institute for Molecular Bioscience at the University of Queensland, Brisbane, Australia, and reported having no relevant financial disclosures. Linda C. Giudice, MD, PhD, is in the department of ob.gyn. and reproductive sciences at the University of California, San Francisco, and reported ties to AbbVie and Bayer. Dr. Montgomery and Dr. Giudice made these remarks in an editorial accompanying Dr. Anglesio’s report (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMe1701700).
The variable patterns of somatic mutations discovered by Anglesio et al. are “intriguing” and raise many questions.
Do specific mutations in deep infiltrating endometriosis lesions contribute to the severity and progression of the disorder? Are such mutations to be found in other types of lesions? In endometrial precursor cells? Do specific mutations account for different presentations in different patients?
Exploring these questions will not be straightforward because of the difficulties in obtaining sufficient endometriotic tissue for genetic studies. Not only is it hard to get samples from peritoneal lesions, but the mutations occur in only one cell type – epithelium – which is even harder to isolate from mixed tissue samples.
Grant W. Montgomery, PhD, is at the Institute for Molecular Bioscience at the University of Queensland, Brisbane, Australia, and reported having no relevant financial disclosures. Linda C. Giudice, MD, PhD, is in the department of ob.gyn. and reproductive sciences at the University of California, San Francisco, and reported ties to AbbVie and Bayer. Dr. Montgomery and Dr. Giudice made these remarks in an editorial accompanying Dr. Anglesio’s report (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMe1701700).
Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.
This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.
All three subtypes of endometriosis exhibit “benign clinical behavior and normal-appearing histologic features,” and are considered to be nonmalignant inflammatory lesions, Dr. Anglesio and his associates said. However, they also “recapitulate some features of malignant neoplasms, including local invasion and resistance to apoptosis,” the investigators noted.
To further explore whether deep infiltrating endometriosis lesions harbor somatic mutations, they performed a series of genetic analyses on samples obtained from three independent cohorts of 27 affected patients in New York, Japan, and Vancouver. Whole-exome sequencing of lesions and adjacent normal tissue from 24 women revealed 80 different somatic mutations in 19 (79%) of the lesions.
The number of mutations per lesion varied widely, from 0 to 17, with a mean of 3.3 mutations per lesion. Five of these lesions harbored mutations in the cancer-driver genes ARID1A, PIK3CA, KRAS, or PPP2R1A.
In targeted-sequencing analyses of samples from three more patients, more activating mutations in the KRAS gene were found in two (66%). One woman had two different activating KRAS mutations, and the other had the same KRAS mutation in three separate lesions.
A further analysis of samples from an additional 12 patients showed KRAS mutations in 3 (25%) of them.
The data indicate that these mutations were very unlikely to have arisen by chance alone. In addition, “because cancer-driver mutations were present only in the epithelium but not the stroma of the same endometriosis lesion, we can assume that the observed mutations provide some key selective advantage to endometriotic epithelial cells,” Dr. Anglesio and his associates said (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMoa1614814).
Their findings are consistent with those of recent studies of other organ systems, which reported cancer-driver mutations in benign lesions and in normal tissues from skin, neuronal, and ovarian samples, they added.
“Our findings challenge the current understanding of this invasive subtype of endometriosis and open the discussion on whether deep infiltrating endometriosis can be considered as a benign neoplasm,” the investigators wrote.
This study was sponsored by 27 nonindustry sources, including the Johns Hopkins University, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ephraim and Wilma Shaw Roseman Foundation, the Endometriosis Foundation of America, and the National Institutes of Health. Dr. Anglesio reported having no relevant financial disclosures; some of his associates reported ties to several industry sources.
Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes, investigators reported in the May 11 issue of the New England Journal of Medicine.
This finding was possible only through the use of a combination of next-generation sequencing tools, together with highly sensitive digital genomic assays. A finding of cancer-related mutations in noncancerous lesions – and, “in particular, in nonovarian deep infiltrating lesions that rarely (if ever) transform into cancer” – was very “surprising” and raises new questions about the pathobiology of endometriosis, said Michael S. Anglesio, PhD, of the University of British Columbia, Vancouver, and his associates.
All three subtypes of endometriosis exhibit “benign clinical behavior and normal-appearing histologic features,” and are considered to be nonmalignant inflammatory lesions, Dr. Anglesio and his associates said. However, they also “recapitulate some features of malignant neoplasms, including local invasion and resistance to apoptosis,” the investigators noted.
To further explore whether deep infiltrating endometriosis lesions harbor somatic mutations, they performed a series of genetic analyses on samples obtained from three independent cohorts of 27 affected patients in New York, Japan, and Vancouver. Whole-exome sequencing of lesions and adjacent normal tissue from 24 women revealed 80 different somatic mutations in 19 (79%) of the lesions.
The number of mutations per lesion varied widely, from 0 to 17, with a mean of 3.3 mutations per lesion. Five of these lesions harbored mutations in the cancer-driver genes ARID1A, PIK3CA, KRAS, or PPP2R1A.
In targeted-sequencing analyses of samples from three more patients, more activating mutations in the KRAS gene were found in two (66%). One woman had two different activating KRAS mutations, and the other had the same KRAS mutation in three separate lesions.
A further analysis of samples from an additional 12 patients showed KRAS mutations in 3 (25%) of them.
The data indicate that these mutations were very unlikely to have arisen by chance alone. In addition, “because cancer-driver mutations were present only in the epithelium but not the stroma of the same endometriosis lesion, we can assume that the observed mutations provide some key selective advantage to endometriotic epithelial cells,” Dr. Anglesio and his associates said (N Engl J Med. 2017 May 11. doi: 10.1056/NEJMoa1614814).
Their findings are consistent with those of recent studies of other organ systems, which reported cancer-driver mutations in benign lesions and in normal tissues from skin, neuronal, and ovarian samples, they added.
“Our findings challenge the current understanding of this invasive subtype of endometriosis and open the discussion on whether deep infiltrating endometriosis can be considered as a benign neoplasm,” the investigators wrote.
This study was sponsored by 27 nonindustry sources, including the Johns Hopkins University, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ephraim and Wilma Shaw Roseman Foundation, the Endometriosis Foundation of America, and the National Institutes of Health. Dr. Anglesio reported having no relevant financial disclosures; some of his associates reported ties to several industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Deep infiltrating endometriosis lesions were found to harbor several genetic mutations, including well-known cancer-driver mutations in the ARID1A, PIK3CA, KRAS, and PPP2R1A genes.
Major finding: Endometriosis samples from 24 women revealed 80 different somatic mutations in 19 (79%) of the lesions; the number of mutations per lesion varied widely, from 0 to 17, with a mean of 3.3 mutations per lesion.
Data source: A series of genetic analyses of archived endometriosis samples from 27 women, and an additional analysis of KRAS mutations in samples from 12 more women.
Disclosures: This study was sponsored by 27 nonindustry sources, including Johns Hopkins University, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ephraim and Wilma Shaw Roseman Foundation, the Endometriosis Foundation of America, and the National Institutes of Health. Dr. Anglesio reported having no relevant financial disclosures; some of his associates reported ties to several industry sources.