Abstract
In the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of the female genital tract most frequently described are ovarian and endometrial cancers. Surgical findings and histopathological examination aimed at resolving this conundrum may be aided by molecular analyses, although they are too often inconclusive. High mitochondrial DNA (mtDNA) variability and its propensity to accumulate mutations has been proposed by our group as a tool to define clonality. We showed mtDNA sequencing to be informative in synchronous primary ovarian and endometrial cancer, detecting tumor-specific mutations in both lesions, ruling out independence of the two neoplasms, and indicating clonality. Furthermore, we tested this method in another frequent simultaneously detected gynecological lesion type, borderline ovarian cancer and their peritoneal implants, which may be monoclonal extra-ovarian metastases or polyclonal independent masses. The purpose of this review is to provide an update on the potential use of mtDNA sequencing in distinguishing independent and metastatic lesions in gynecological cancers, and to compare the efficiency of molecular analyses currently in use with this novel method.
Highlights
Tumors of the female genitalia are a heterogeneous group of disease with different prognosis even when originating from the same organ such as the uterus and ovary
A higher propensity of mitochondrial DNA (mtDNA) to accumulate mutations than nuclear DNA is an additional hallmark that can be exploited for diagnostic purposes; this is due both to the heteroplasmic nature of mutations, that may coexist with wild-type mtDNA copies without triggering a phenotypic response, to the proximity of the mtDNA molecules to reactive oxygen species (ROS)-generating sites such as the respiratory complexes, accompanied by a lower capacity of DNA repair coupled with a high frequency of replicative errors
Our results showed that mtDNA genotyping may provide a substantial contribution to recognize the metastatic nature of simultaneously detected endometrial cancer (EC) and ovarian cancer (OC), helping in understanding the staging and clinical management of these patients
Summary
Tumors of the female genitalia are a heterogeneous group of disease with different prognosis even when originating from the same organ such as the uterus and ovary. Multiple synchronous gynecological lesions represent 1–2% of cases [1,2,3]: in this scenario, clinicians have to face the diagnostic problem of whether the simultaneous malignancies arise independently or as a result of metastatic dissemination [4,5]. This distinction is important especially with epithelial ovarian cancer, which accounts for the highest mortality among gynecological tumors [6,7]. The purpose of this review is to give an overview on the exploitation of mtDNA variability in gynecological malignancies in a critical comparison with currently implemented molecular analyses. mtDNA sequencing, as a method to detect synchronous lesions among gynecological tumors, has been previously tested by our group to tackle the two previously mentioned clinical issues: to distinguish simultaneous versus metastatic EC/OC [17] and to demonstrate clonality of peritoneal implants of BOT [18]
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