Histological Diagnosis of Polyploidy Discriminates an Aggressive Subset of Hepatocellular Carcinomas with Poor Prognosis

Overview

Journal Br J Cancer

Specialty Oncology

Date 2023 Sep 15

PMID 37715023

Authors

Takanori Matsuura

Yoshihide Ueda

Yoshiyuki Harada

Kazuki Hayashi

Kisara Horisaka

Yoshihiko Yano

Shinichi So

Masahiro Kido

Takumi Fukumoto

Yuzo Kodama

Eiji Hara

Tomonori Matsumoto

Affiliations

Soon will be listed here.

Abstract

Background: Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is unclear. We aimed to determine the characteristics of polyploid HCCs by evaluating chromosome duplication and to discover surrogate markers to discriminate polyploid HCCs.

Methods: The ploidy in human HCC was assessed by fluorescence in situ hybridization for multiple chromosomes. Clinicopathological and expression features were compared between polyploid and near-diploid HCCs. Markers indicating polyploid HCC were explored by transcriptome analysis of cultured HCC cells.

Results: Polyploidy was detected in 36% (20/56) of HCCs and discriminated an aggressive subset of HCC that typically showed high serum alpha-fetoprotein, poor differentiation, and poor prognosis compared to near-diploid HCCs. Molecular subtyping revealed that polyploid HCCs highly expressed alpha-fetoprotein but did not necessarily show progenitor features. Histological examination revealed abundant polyploid giant cancer cells (PGCCs) with a distinct appearance and frequent macrotrabecular-massive architecture in polyploid HCCs. Notably, the abundance of PGCCs and overexpression of ubiquitin-conjugating enzymes 2C indicated polyploidy in HCC and efficiently predicted poor prognosis in combination.

Conclusions: Histological diagnosis of polyploidy using surrogate markers discriminates an aggressive subset of HCC, apart from known HCC subgroups, and predict poor prognosis in HCC.

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References

Ng I, Lai E, Ho J, Cheung L, Ng M, So M . Flow cytometric analysis of DNA ploidy in hepatocellular carcinoma. Am J Clin Pathol. 1994; 102(1):80-6. DOI: 10.1093/ajcp/102.1.80. View

Niu N, Mercado-Uribe I, Liu J . Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells. Oncogene. 2017; 36(34):4887-4900. PMC: 5582213. DOI: 10.1038/onc.2017.72. View

Sakaue-Sawano A, Yo M, Komatsu N, Hiratsuka T, Kogure T, Hoshida T . Genetically Encoded Tools for Optical Dissection of the Mammalian Cell Cycle. Mol Cell. 2017; 68(3):626-640.e5. DOI: 10.1016/j.molcel.2017.10.001. View

Steele C, Abbasi A, Islam S, Bowes A, Khandekar A, Haase K . Signatures of copy number alterations in human cancer. Nature. 2022; 606(7916):984-991. PMC: 9242861. DOI: 10.1038/s41586-022-04738-6. View

Zeng S, Yamashita T, Kondo M, Nio K, Hayashi T, Hara Y . The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. J Hepatol. 2013; 60(1):127-34. DOI: 10.1016/j.jhep.2013.08.024. View

Toyoda H, Bregerie O, Vallet A, Nalpas B, Pivert G, Brechot C . Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut. 2005; 54(2):297-302. PMC: 1774850. DOI: 10.1136/gut.2004.043893. View

Zhang L, Yang Z, Zhang S, Zhou K, Zhang W, Ling S . Polyploidy Spectrum Correlates with Immunophenotype and Shapes Hepatocellular Carcinoma Recurrence Following Liver Transplantation. J Inflamm Res. 2022; 15:217-233. PMC: 8760994. DOI: 10.2147/JIR.S345681. View

Masuda S, Suzuki K, Izpisua Belmonte J . Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med. 2013; 369(12):1171. DOI: 10.1056/NEJMc1308785. View

Sikora E, Czarnecka-Herok J, Bojko A, Sunderland P . Therapy-induced polyploidization and senescence: Coincidence or interconnection?. Semin Cancer Biol. 2020; 81:83-95. DOI: 10.1016/j.semcancer.2020.11.015. View

10.

Gerstung M, Jolly C, Leshchiner I, Dentro S, Gonzalez S, Rosebrock D . The evolutionary history of 2,658 cancers. Nature. 2020; 578(7793):122-128. PMC: 7054212. DOI: 10.1038/s41586-019-1907-7. View

11.

Prasad K, Bloomfield M, Levi H, Keuper K, Bernhard S, Baudoin N . Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers. Cancer Res. 2022; 82(9):1736-1752. PMC: 9069772. DOI: 10.1158/0008-5472.CAN-21-2065. View

12.

Rebouissou S, Nault J . Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020; 72(2):215-229. DOI: 10.1016/j.jhep.2019.08.017. View

13.

Wangsa D, Quintanilla I, Torabi K, Vila-Casadesus M, Ercilla A, Klus G . Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness. FASEB J. 2018; 32(7):3502-3517. PMC: 5998968. DOI: 10.1096/fj.201700247RR. View

14.

Matsumoto T . Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers. Int J Mol Sci. 2022; 23(16). PMC: 9409051. DOI: 10.3390/ijms23169409. View

15.

Carter S, Cibulskis K, Helman E, McKenna A, Shen H, Zack T . Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012; 30(5):413-21. PMC: 4383288. DOI: 10.1038/nbt.2203. View

16.

Taylor A, Shih J, Ha G, Gao G, Zhang X, Berger A . Genomic and Functional Approaches to Understanding Cancer Aneuploidy. Cancer Cell. 2018; 33(4):676-689.e3. PMC: 6028190. DOI: 10.1016/j.ccell.2018.03.007. View

17.

Bielski C, Zehir A, Penson A, Donoghue M, Chatila W, Armenia J . Genome doubling shapes the evolution and prognosis of advanced cancers. Nat Genet. 2018; 50(8):1189-1195. PMC: 6072608. DOI: 10.1038/s41588-018-0165-1. View

18.

Darzynkiewicz Z . Critical aspects in analysis of cellular DNA content. Curr Protoc Cytom. 2011; Chapter 7:7.2.1-7.2.8. PMC: 3238682. DOI: 10.1002/0471142956.cy0702s56. View

19.

Boyault S, Rickman D, De Reynies A, Balabaud C, Rebouissou S, Jeannot E . Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2006; 45(1):42-52. DOI: 10.1002/hep.21467. View

20.

Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouze E, Blanc J . Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017; 67(4):727-738. DOI: 10.1016/j.jhep.2017.05.014. View