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Genomic alterations in gynecological malignancies: histotype-associated driver mutations, molecular subtyping schemes, and tumorigenic mechanisms

Journal of Human Genetics volume 66, pages 853–868 (2021)Cite this article

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Abstract

There are numerous histological subtypes (histotypes) of gynecological malignancies, with each histotype considered to largely reflect a feature of the “cell of origin,” and to be tightly linked with the clinical behavior and biological phenotype of the tumor. The recent advances in massive parallel sequencing technologies have provided a more complete picture of the range of the genomic alterations that can persist within individual tumors, and have highlighted the types and frequencies of driver-gene mutations and molecular subtypes often associated with these histotypes. Several large-scale genomic cohorts, including the Cancer Genome Atlas (TCGA), have been used to characterize the genomic features of a range of gynecological malignancies, including high-grade serous ovarian carcinoma, uterine corpus endometrial carcinoma, uterine cervical carcinoma, and uterine carcinosarcoma. These datasets have also been pivotal in identifying clinically relevant molecular targets and biomarkers, and in the construction of molecular subtyping schemes. In addition, the recent widespread use of clinical sequencing for the more ubiquitous types of gynecological cancer has manifested in a series of large genomic datasets that have allowed the characterization of the genomes, driver mutations, and histotypes of even rare cancer types, with sufficient statistical power. Here, we review the field of gynecological cancer, and seek to describe the genomic features by histotype. We also will demonstrate how these are linked with clinicopathological attributes and highlight the potential tumorigenic mechanisms.

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Acknowledgements

The authors thank Rebecca Jackson for editing a draft of this manuscript. This work was supported by JSPS KAKENHI; Grant Numbers JP17K18337, JP15K06861, JP18K07338, JP26462543, and JP17K11308 and by the Vehicle Racing Commemorative Foundation; Grant Numbers 5144, 5274, and 5393.

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  1. Project for Development of Innovative Research on Cancer Therapeutics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Seiichi Mori & Osamu Gotoh

  2. Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Kazuma Kiyotani & Siew Kee Low

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Mori, S., Gotoh, O., Kiyotani, K. et al. Genomic alterations in gynecological malignancies: histotype-associated driver mutations, molecular subtyping schemes, and tumorigenic mechanisms. J Hum Genet 66, 853–868 (2021). https://doi.org/10.1038/s10038-021-00940-y

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