Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer

Jeremy Chien, Lisa Neums, Alexis F.L.A. Powell, Michelle Torres, Kimberly R. Kalli, Francesco Multinu, Vijayalakshmi Shridhar, Andrea Mariani

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Article number58
JournalFrontiers in Oncology
Volume8
Issue numberMAR
DOIs
StatePublished - Mar 7 2018

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Carcinoma
Neoplasms
Phylogeny
Neoplasm Metastasis
Nucleotides
Clone Cells
Gene Frequency
Mutation

Keywords

  • Cancer genomics
  • Intratumor heterogeneity
  • Ovarian cancers
  • Peritoneal spread
  • Phylogenetic analysis
  • Progression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chien, J., Neums, L., Powell, A. F. L. A., Torres, M., Kalli, K. R., Multinu, F., ... Mariani, A. (2018). Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer. Frontiers in Oncology, 8(MAR), [58]. https://doi.org/10.3389/fonc.2018.00058

Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer. / Chien, Jeremy; Neums, Lisa; Powell, Alexis F.L.A.; Torres, Michelle; Kalli, Kimberly R.; Multinu, Francesco; Shridhar, Vijayalakshmi; Mariani, Andrea.

In: Frontiers in Oncology, Vol. 8, No. MAR, 58, 07.03.2018.

Research output: Contribution to journalArticle

Chien, J, Neums, L, Powell, AFLA, Torres, M, Kalli, KR, Multinu, F, Shridhar, V & Mariani, A 2018, 'Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer', Frontiers in Oncology, vol. 8, no. MAR, 58. https://doi.org/10.3389/fonc.2018.00058
Chien J, Neums L, Powell AFLA, Torres M, Kalli KR, Multinu F et al. Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer. Frontiers in Oncology. 2018 Mar 7;8(MAR). 58. https://doi.org/10.3389/fonc.2018.00058
Chien, Jeremy ; Neums, Lisa ; Powell, Alexis F.L.A. ; Torres, Michelle ; Kalli, Kimberly R. ; Multinu, Francesco ; Shridhar, Vijayalakshmi ; Mariani, Andrea. / Genetic evidence for early peritoneal spreading in pelvic high-grade serous cancer. In: Frontiers in Oncology. 2018 ; Vol. 8, No. MAR.
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AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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