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Separate Research Teams Find Evidence of Clonality in SEO Cancer Tumors

NEW YORK (GenomeWeb) – A pair of recently published studies has provided strong evidence that each pair of synchronous endometrial and ovarian (SEO) cancer tumors are in fact genetically related clones.

The studies, published in January in the Journal of the National Cancer Institute, provide new insight into a little-understood type of metastasis, and have implications regarding the potential treatment of these cancers.

SEO tumors behave as if they are independent, localized early-stage tumors that often respond well to surgery alone. The spread of a tumor from one organ to another is virtually always an indication of an advanced stage cancer that requires aggressive treatment, but the difficulty in determining whether SEO cancer is metastatic has led to widely differing treatments.

In order to gain a better understanding of synchronous organ tumors in endometrial and ovarian cancer cases, a team led by scientists at the British Columbia Cancer Agency and the University of British Columbia sequenced 35 frequently mutated cancer genes in 18 pairs of SEO tumors donated by nine patients.  They reviewed the patient's medical history to give some indication on whether or not metastasis was suspected. The samples were analyzed using targeted and exome sequencing.

The researchers obtained exome data for five patient cases, four of which showed multiple concordant shared mutations between exome and deep sequencing. They determined based on comparing DNA copy number and allelic frequency plots generated from the exome data that in three of the five patient cases they were seeing a pattern consistent with clonal copy number and loss of heterozygosity changes — essentially meaning that these tumors were developing at the same time and were not necessarily an indication of late-stage cancer.

The apparent paradox of the same cancer appearing simultaneously as two independent early-stage tumors on two different organs seems to be invoking "pseudo-metastasis," the researchers said in a statement. This is distinct from usual metastasis since the cancer likely spreads through the fallopian tube, not the blood stream, which is a unique environment provided by this particular organ.

"Pseudo-metastasis is still something of a mystery," lead author and research associate in the department of Molecular Oncology at the BC Cancer Agency, Michael Anglesio said in a statement. "Whether the initial event takes place in the ovary or the endometrium, and what keeps cells temporarily restricted to these special organs without metastasizing to the rest of the body, are things that we are now researching."

The identification of pseudo-metastasis has important implications for treatment. On a global scale, many women with SEO tumors have received aggressive treatment designed to fight late-stage metastatic cancer. Physicians in British Columbia have generally treated SEO cancer patients more conservatively and surgically removed the tumors, which the researchers claim would be the best course of action according to their findings.

The researchers noted in the paper that the small cohort size in this study does indicate a need for further investigation of the pseudo-metastasis mechanisms to determine whether this seems to be consistent on a larger scale.

In the second JNCI study, researchers based at Memorial Sloan Kettering Cancer also observed that something other than normal metastasis was at work in SEO cancer cases.

The MSKCC researchers collected a series of 23 synchronous endometrioid endometrial carcinomas (EECs) and endometrioid ovarian carcinomas (EOCs) that were histologically reviewed. Then they extracted DNA from all of the samples and subjected the first five samples to whole-exome sequencing and orthogonal validation using high-depth targeted amplicon resequencing. The remaining 18 samples were subjected to massively parallel sequencing (MPS).

After comparing the mutational spectra and context of the mutations present in both EECs and EOCs, the researchers observed that the mutational processes didn't vary between tumors from each of the patients analyzed, which seemed to indicate clonality. They decided to confirm the generalizability of their initial findings by subjecting a series of 17 sporadic synchronous EECs/EOCs and one Lynch Syndrome case to targeted capture MPS. This analysis still led the MSKCC research team to conclude that these tumor cases were clonally linked.

The synchronous findings give both research teams confidence that their findings and recommendations for less aggressive treatment for SEO cancer patients seem sound. An editorial piece also published in the JNCI also stated that since these findings came from two different groups, it would suggest that "SEOs are not independent but rather represent isolated metastatic phenomenon."

"Together, these studies have resulted in a paradigm shift in the way SEO cancers are perceived," assistant member of the department of pathology at MSKCC, Britta Weigelt said in a statement. "By bringing together pathology and genetics, we have solved a long-standing biological question and clinical dilemma."

The study was funded by the Gray Family Ovarian Clear Cell Carcinoma Research Resource, the BC Cancer Foundation, the Vancouver General Hospital and UBC Hospital Foundation, and the Canadian Cancer Society.