Abstract

Most pelvic high-grade serous (HGS) carcinomas have been proposed to arise from tubal primaries that progress rapidly to advanced disease. However, the temporal sequence of ovarian and peritoneal metastases is not well characterized. To establish the sequence of metastases, phylogenetic relationships among the ovarian and peritoneal carcinomas were determined from single-nucleotide variations (SNVs) in nine tumor regions from each patient with pelvic HGS carcinomas. Somatic SNVs from each tumor sample were used to reconstruct phylogenies of samples from each patient. Variant allele frequencies were used to reconstruct subclone phylogenies in each tumor sample. We show that pelvic HGS carcinomas are highly heterogeneous, only sharing less than 4% of somatic SNVs among all nine carcinoma implants in one patient. TP53 mutations are found in all nine carcinoma implants in each patient. The phylogenetic analyses reveal that peritoneal metastases arose from early branching events that preceded branching events for ovarian carcinomas in some patients. Finally, subclone phylogenies indicate the presence of multiple subclones at each tumor implant and early tumor clones in peritoneal implants. The genetic evidence that peritoneal implants arose before or concurrently with ovarian implants is consistent with the emerging concept of the extra-ovarian origin of pelvic HGS cancer. Our results challenge the concept of stepwise spatial progression from the fallopian primary to ovarian carcinomas to peritoneal dissemination and suggest an alternative progression model where peritoneal spreading of early clones occurs before or in parallel with ovarian metastases.

Highlights

  • The primary ovarian, peritoneal, and fallopian tube high-grade serous (HGS) carcinomas are inclusively categorized as the HGS carcinomas of the pelvis [1]

  • Pelvic HGS carcinomas may progress in a stepwise fashion from the primary lesions in the fallopian tube to the ovarian carcinomas to peritoneal metastases

  • We used somatic single-nucleotide variations (SNVs) to reconstruct phylogenetic trees of tumor samples and tumor subclones within each tumor samples. These analyses provided genetic evidence that early-evolved tumor clones in pelvic HGS carcinoma contribute to peritoneal metastases

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Summary

Introduction

The primary ovarian, peritoneal, and fallopian tube HGS carcinomas are inclusively categorized as the HGS carcinomas of the pelvis [1]. The ovary was previously considered as the primary for Peritoneal Spreading in Ovarian Cancer these carcinomas, emerging pathologic evidence suggests that the fallopian tube is the primary site for most pelvic HGS carcinomas [1]. Mathematical models based on clinical evidence suggest pelvic HGS carcinomas progress rapidly to disseminated disease [7]. Pelvic HGS carcinomas may progress in a stepwise fashion from the primary lesions in the fallopian tube to the ovarian carcinomas to peritoneal metastases. Most pelvic high-grade serous (HGS) carcinomas have been proposed to arise from tubal primaries that progress rapidly to advanced disease. The temporal sequence of ovarian and peritoneal metastases is not well characterized

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