Skip to main content
Premium Trial:

Request an Annual Quote

Endometriosis Sequences Suggest Subset Contains Mutations to Cancer-Related Genes

NEW YORK (GenomeWeb) – A new study suggests that some deeply infiltrating endometriosis samples contain somatic mutations in cancer driver genes, despite the lack of malignancy associated with these lesions.

"[A]though endometriosis is considered to be a benign disorder from both a clinical and a histopathological perspective, well-known cancer-associated somatic mutations were found in the glandular epithelium of some deep infiltrating endometriosis lesions," wrote the authors of the study, published yesterday in the New England Journal of Medicine.

The team, led by investigators at Johns Hopkins University, the BC Cancer Agency, and the BC Women's Hospital and Health Centre, used a combination of exome sequencing and targeted sequencing to profile mutation patterns in infiltrating endometriotic lesions from dozens of women. The search uncovered mutations in five known cancer contributors, leading to further testing of one of these, KRAS, in additional endometriosis cases.

Such results suggest that there may be "new opportunities for a more detailed examination of all forms of endometriosis with the use of research approaches that are common in the study of cancer," the authors noted.

The researchers started by using Bio-Rad droplet digital PCR to assess non-ovarian, infiltrating endometriosis cases, focusing in on formalin-fixed, paraffin-embedded endometriotic lesion samples from 24 women for exome sequencing. After capturing protein-coding portions of the genomes with Agilent SureSelect kits, they sequenced the exomes with Illumina instruments, generating average exome coverage of 104-fold.

By considering the endometriosis sequences alongside exomes from matched normal samples from each individual, the team uncovered anywhere from zero to 17 non-synonymous somatic mutations per lesion. In five of the women, those mutations fell in the known cancer driver genes KRAS, ARID1A, PIK3CA, or PPP2R1A — findings confirmed with immunohistochemistry and so-called Safe-SeqS analyses.

"We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer," co-first author Nicholas Papadopoulos, an oncology and pathology researcher at Johns Hopkins, said in a statement. "We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread."

To explore such patterns in more detail, the researchers turned to approaches such as panel sequencing and droplet digital PCR to profile KRAS in still more endometriosis cases, identifying KRAS mutations in epithelial tissue but not stroma in five of 15 cases.

The study's authors noted that "given an estimated rate of malignant transformation for endometriosis close to [1 percent], our results suggest that the presence of driver mutations alone is neither sufficient to drive the transformation of endometriosis nor indicative of likely progression to cancer."

Even so, the researchers suggested that more research is needed to understand if, and how, alterations in such genes might contribute to the aggressiveness of endometriosis cases and the degree to which they invade other tissues.

"Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not," co-senior author Ie-Ming Shih, a gynecology and obstetric researcher and co-director of the Johns Hopkins breast and ovarian cancer program, said in a statement.