Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

Abstract

Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Recognition of synchrony upon multiple tumors is crucial for correct prognosis, therapeutic choice, and patient management. Current guidelines for determining synchrony, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. However, because of the uniqueness of each tumor and of its intrinsic heterogeneity, these analyses may sometimes be inconclusive. A role for mitochondrial DNA genotyping was previously demonstrated in the diagnosis of synchronous endometrial and ovarian carcinoma. We have analyzed 11 sample pairs of simultaneously revealed endometrial and ovarian cancers and have thereby applied conventional histopathological criteria, current molecular analyses (microsatellite instability, b-catenin immunohistochemical staining/CTNNB1 mutation screening), and mitochondrial DNA sequencing to distinguish separate independent tumors from metastases, comparing the performance and the informative potential of such methods. We have demonstrated that in ambiguous interpretations where histopathological criteria and canonical molecular methods fail to be conclusive, mitochondrial DNA analysis may act as a needle of balance and allow to formulate a diagnosis in 45.5% of our cases. Additional advantages of mitochondrial DNA genotyping, besides the high level of information we demonstrated here, are the easy implementation and the need for small amounts of starting material. Our results show that mitochondrial DNA genotyping may provide a substantial contribution to indisputably recognize the metastatic nature of simultaneously detected endometrial and ovarian cancers and may change the final staging and clinical management of these patients. Modern Pathology (2014) 27, 1412-1420; doi:10.1038/modpathol.2014.39; published online 14 March 2014 Keywords: gynecological cancer; mitochondrial DNA mutations; synchronous tumors About 1-2% of women with gynecological cancers are found to have simultaneous independent primary malignancies. Synchronous tumors in the ovary and endometrium are the commonest combination (50-70%) among all synchronous female genital tract malignancies. Only a subset of these can be accurately categorized by standard histological examination. Criteria for synchrony diagnosis were first documented in 1985 1 and subsequently detailed in 1998. 2 Unfortunately, a relevant fraction of cases remains which may not be classified with confidence, either because of widespread involvement, in which case the distinction is of academic rather than practical or prognostic significance, or, more importantly, because of overlapping or

Synchronous Endometrial and Ovarian Carcinoma: A Case Series

“…It is also believed that embryologically similar tissues such as those of the female genital tract are affected from hormonal stimulation and other carcinogenic factors [ 12 ]. Additionally by analyzing mitochondrial DNA and by sequencing different genes, a clonality of SEOCs was confirmed [ 13 , 14 ]. Nuclear localization of β-catenin and presence of CTNNB1 mutations are associated with SEOC [ 15 ].…”

Mitochondrial changes in endometrial carcinoma: Possible role in tumor diagnosis and prognosis (Review)

“…Histopathological criteria and canonical molecular analysis such as microsatellite instability, B-catenin immunohistochemical staining and CTNNB1 mutation screening provided ambiguous diagnoses in certain cases. The mtDNA genotype approach allowed to define the diagnosis in half of the analyzed cases (75). This new molecular approach has the advantages of requiring small amounts of starting material and has relatively low costs.…”

Pathological and molecular diagnosis of bilateral inguinal lymph nodes metastases from low-grade endometrial adenocarcinoma: a case report with review of the literature

“…A control (non tumor) DNA specimen was obtained from the patient’s saliva after collection of informed consent. Whole mtDNA sequencing was performed on EC, metastatic inguinal lymph node and saliva-derived total DNA as previously described [ 5 – 7 ]. We used a PCR-based resequencing system which enables identification of sequence variations in the entire human mitochondrial genome and its control region.…”

“…The diagnosis of inguinal LNI from EC was performed by standard histological analysis on lymph node dissection specimens. Moreover, the recently validated method of mitochondrial DNA (mtDNA) sequencing [ 5 ] was used to confirmed the clonality of EC lesions.…”