Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Abstract

BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

Pathogenesis of endometriosis: the genetic/epigenetic theory

“…Endometriosis lesions have an altered biology. Local estrogen production (154) (186,187). These changes are increasingly viewed as a consequence of genetic or epigenetic polymorphism (154,(188)(189)(190).…”

The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

“…In fact, even for adenomyosis, there might be two or more different pathogenic origins, for example, the FAOM, or extrinsic or external adenomyosis, might originate from the invasion of neighboring DE lesions. Future phylogenic analysis based on the next-generation sequencing should be able to resolve this issue [101]. Even within the framework of the TIAR theory, endometriosis also originates from the microtraumatization, and the pathogenesis seems to be different from that of adenomyosis.…”

How Benign is Endometriosis: Multi-Scale Interrogation of Documented Evidence

“…The 'driver genes' like ARID1A, PIK3CA, KRAS, PPP2R1A and TP53 are reportedly present in benign, nonmalignant settings and thus the issue of oncogenicity needs to be considered in tissue context-dependent manner [165]. Guo [166] suggests that a web of gene expressions anchored by the set of driver genes, (e.g. TP53, PTEN, ARID1A, PIK3CA, KRAS and PPP2R1A, CDKN2A, NF2 and NOTCH1) are likely to be involved in inducing EMT and progressive fibrogenesis in ET lesions.…”

“…TP53, PTEN, ARID1A, PIK3CA, KRAS and PPP2R1A, CDKN2A, NF2 and NOTCH1) are likely to be involved in inducing EMT and progressive fibrogenesis in ET lesions. Cyclic bleeding associated with inflammatory and oxidative stress followed by subsequent tissue repair similar to that occurring in EE may be viewed as wounds that undergo repeated tissue injury followed by repair along with recurrent estrogenic stimulation and ovulatory events which in the pelvic environment lead to smooth muscle metaplasia (SMM) and fibrogenesis associated with epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast trans-differentiation (FMT), and tumorigenesis especially in high risk patients [166][167][168][169].…”