Gene amplification of chromatin remodeling factor <em>SMARCC2</em> and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

Magarifuchi,Naomi; Magarifuchi,Naomi; Iwasaki,Takeshi; Iwasaki,Takeshi; Katayama,Yoshihiro; Katayama,Yoshihiro; Tomonaga,Takumi; Tomonaga,Takumi; Nakashima,Miya; Nakashima,Miya; Narutomi,Fumiya; Narutomi,Fumiya; Kato,Kiyoko; Kato,Kiyoko; Oda,Yoshinao; Oda,Yoshinao

doi:10.3892/ol.2024.14329

Gene amplification of chromatin remodeling factor SMARCC2 and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

Authors:
- Naomi Magarifuchi
- Takeshi Iwasaki
- Yoshihiro Katayama
- Takumi Tomonaga
- Miya Nakashima
- Fumiya Narutomi
- Kiyoko Kato
- Yoshinao Oda
View Affiliations

Affiliations: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812‑8582, Japan, Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812‑8582, Japan
Published online on: March 7, 2024 https://doi.org/10.3892/ol.2024.14329
Article Number: 196

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ovarian high‑grade serous carcinoma (OHGSC) is the most common type of ovarian cancer worldwide. Genome sequencing has identified mutations in chromatin remodeling factors (CRFs) in gynecological cancer, such as clear cell carcinoma, endometrioid carcinoma and endometrial serous carcinoma. However, to the best of our knowledge, the association between CRFs and OHGSC remains unexplored. The present study aimed to investigate the clinicopathological and molecular characteristics of CRF dysfunction in OHGSC. CRF alterations were analyzed through numerous methods, including the analysis of public next‑generation sequencing (NGS) data from 585 ovarian serous carcinoma cases from The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC), and DNA copy number assays, which were performed on 203 surgically resected OHGSC samples. In the public NGS dataset, the most frequent genetic alteration was actin‑like protein 6A (ACTL6A) amplification at 19.5%. Switch/sucrose non‑fermentable related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2) amplification (3.1%) was associated with significantly decreased overall survival (OS). In addition, chromodomain‑helicase‑DNA‑binding protein 4 (CHD4) amplification (5.7%) exhibited unfavorable outcome trends, although not statistically significant. IHC revealed the protein expression loss of ARID1A (2.5%), SMARCA2 (2.5%) and SMARCA4 (3.9%). The protein expression levels of ACTL6A, SMARCC2 and CHD4 were evaluated using H‑score. Patients with low protein expression levels of ACTL6A showed a significantly decreased OS. Copy number gain or gene amplification was demonstrated in ACTL6A (66.2%) and SMARCC2 (33.5%), while shallow deletion or deep deletion was demonstrated in CHD4 (70.7%). However, there was no statistically significant difference in protein levels of these CRFs, between the different copy number alterations (CNAs). Overall, OHGSC exhibited CNAs and protein loss, indicating possible gene alterations in CRFs. Moreover, there was a significant association between the protein expression levels of ACTL6A and poor prognosis. Based on these findings, it is suggested that CRFs could serve as prognostic markers for OHGSC.

View Figures

View References

1	Kim J, Park EY, Kim O, Schilder JM, Coffey DM, Cho CH and Bast RC Jr: Cell origins of high-grade serous ovarian cancer. Cancers (Basel). 10:4332018. View Article : Google Scholar : PubMed/NCBI
2	Peres LC, Cushing-Haugen KL, Köbel M, Harris HR, Berchuck A, Rossing MA, Schidkraut JM and Doherty JA: Invasive epithelial ovarian cancer survival by histotype and disease stage. J Natl Cancer Inst. 111:60–68. 2019. View Article : Google Scholar : PubMed/NCBI
3	Barlin JN, Long KC, Tanner EJ, Gardner GJ, Leitao MM Jr, Levine DA, Sonoda Y, Abu-Rustum NR, Barakat RR and Chi DS: Optimal (≤1 cm) but visible residual disease: Is extensive debulking warranted? Gynecol Oncol. 130:284–288. 2013. View Article : Google Scholar : PubMed/NCBI
4	Dao F, Schlappe BA, Tseng J, Lester J, Nick AM, Lutgendorf SK, McMeekin S, Coleman RL, Moore KN, Karlan BY, et al: Characteristics of 10-year survivors of high-grade serous ovarian carcinoma. Gynecol Oncol. 141:260–263. 2016. View Article : Google Scholar : PubMed/NCBI
5	Iacobuzio-Donahue CA: Epigenetic changes in cancer. Annu Rev Pathol. 4:229–249. 2009. View Article : Google Scholar : PubMed/NCBI
6	Baylin SB and Jones PA: Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 8:a0195052016. View Article : Google Scholar : PubMed/NCBI
7	Hasan N and Ahuja N: The emerging roles of ATP-dependent chromatin remodeling complexes in pancreatic cancer. Cancers (Basel). 11:18592019. View Article : Google Scholar : PubMed/NCBI
8	Kadoch C and Crabtree GR: Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 1:e15004472015. View Article : Google Scholar : PubMed/NCBI
9	Khalique S, Naidoo K, Attygalle AD, Kriplani D, Daley F, Lowe A, Campbell J, Jones T, Hubank M, Fenwick K, et al: Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers. Pathol Clin Res. 4:154–166. 2018. View Article : Google Scholar : PubMed/NCBI
10	Le Gallo M, O'Hara AJ, Rudd ML, Urick ME, Hansen NF, O'Neil NJ, Price JC, Zhang S, England BM, Godwin AK, et al: Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 44:1310–1315. 2012. View Article : Google Scholar : PubMed/NCBI
11	Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, et al: ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 363:1532–1543. 2010. View Article : Google Scholar : PubMed/NCBI
12	Ramos P, Karnezis AN, Craig DW, Sekulic A, Russell ML, Hendricks WPD, Corneveaux JJ, Barrett MT, Shumansky K, Yang Y, et al: Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet. 46:427–429. 2014. View Article : Google Scholar : PubMed/NCBI
13	Oyama Y, Shigeta S, Tokunaga H, Tsuji K, Ishibashi M, Shibuya Y, Shimada M, Yasuda J and Yaegashi N: CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents. PLoS One. 16:e02510792021. View Article : Google Scholar : PubMed/NCBI
14	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
15	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
16	Cree IA, White VA, Indave BI and Lokuhetty D: Revising the WHO classification: Female genital tract tumours. Histopathology. 76:151–156. 2020. View Article : Google Scholar : PubMed/NCBI
17	Prat J and Oncology FCoG: FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum: Abridged republication. J Gynecol Oncol. 26:87–89. 2015. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Clapier CR, Iwasa J, Cairns BR and Peterson CL: Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol. 18:407–422. 2017. View Article : Google Scholar : PubMed/NCBI
20	He S, Wu Z, Tian Y, Yu Z, Yu J, Wang X, Li J, Liu B and Xu Y: Structure of nucleosome-bound human BAF complex. Science. 367:875–881. 2020. View Article : Google Scholar : PubMed/NCBI
21	Wade SL, Langer LF, Ward JM and Archer TK: MiRNA-mediated regulation of the SWI/SNF chromatin remodeling complex controls pluripotency and endodermal differentiation in human ESCs. Stem Cells. 33:2925–2935. 2015. View Article : Google Scholar : PubMed/NCBI
22	Ramírez J and Hagman J: The Mi-2/NuRD complex: A critical epigenetic regulator of hematopoietic development, differentiation and cancer. Epigenetics. 4:532–536. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zhang J, Shih DJH and Lin SY: The tale of CHD4 in DNA damage response and chemotherapeutic response. J Cancer Res Cell Ther. 3:0522019.PubMed/NCBI
24	Chen PM, Wong CN, Wong CN and Chu PY: Actin-like Protein 6A expression correlates with cancer stem cell-like features and poor prognosis in ovarian cancer. Int J Mol Sci. 24:20162023. View Article : Google Scholar : PubMed/NCBI
25	Ji J, Xu R, Zhang X, Han M, Xu Y, Wei Y, Ding K, Wang S, Huang B, Chen A, et al: Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ. Cell Death Dis. 9:5172018. View Article : Google Scholar : PubMed/NCBI
26	Saladi SV, Ross K, Karaayvaz M, Tata PR, Mou H, Rajagopal J, Ramaswamy S and Ellisen LW: ACTL6A is co-amplified with p63 in squamous cell carcinoma to drive YAP activation, regenerative proliferation, and poor prognosis. Cancer Cell. 31:35–49. 2017. View Article : Google Scholar : PubMed/NCBI
27	Sun W, Wang W, Lei J, Li H and Wu Y: Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma. Oncol Rep. 37:2405–2417. 2017. View Article : Google Scholar : PubMed/NCBI
28	Xiao S, Chang RM, Yang MY, Lei X, Liu X, Gao WB, Xiao JL and Yang LY: Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition. Hepatology. 63:1256–1271. 2016. View Article : Google Scholar : PubMed/NCBI
29	Zeng Z, Yang H and Xiao S: ACTL6A expression promotes invasion, metastasis and epithelial mesenchymal transition of colon cancer. BMC Cancer. 18:10202018. View Article : Google Scholar : PubMed/NCBI
30	Xiao Y, Lin FT and Lin WC: ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer. Proc Natl Acad Sci USA. 118:e20158081182021. View Article : Google Scholar : PubMed/NCBI
31	Buccitelli C and Selbach M: mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 21:630–644. 2020. View Article : Google Scholar : PubMed/NCBI
32	Yamamoto T, Kohashi K, Yamada Y, Kawata J, Sakihama K, Matsuda R, Koga Y, Aishima S, Nakamura M and Oda Y: Relationship between cellular morphology and abnormality of SWI/SNF complex subunits in pancreatic undifferentiated carcinoma. J Cancer Res Clin Oncol. 148:2945–2957. 2022. View Article : Google Scholar : PubMed/NCBI
33	Li C, Wang T, Gu J, Qi S, Li J, Chen L, Wu H, Shi L, Song C and Li H: SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of glioblastoma. Cell Death Dis. 13:9902022. View Article : Google Scholar : PubMed/NCBI
34	Havranek O, Westin JR, Zhang M, Rawal S, Kwak LW, Neelapu SS and Davis RE: Integrated analysis of genomic and gene expression profiles in follicular lymphoma reveals subsets and driver genes of potential microenvironmental importance. Blood. 122:2487–2490. 2013. View Article : Google Scholar
35	Hu B, Lin JZ, Yang XB and Sang XT: The roles of mutated SWI/SNF complexes in the initiation and development of hepatocellular carcinoma and its regulatory effect on the immune system: A review. Cell Prolif. 53:e127912020. View Article : Google Scholar : PubMed/NCBI
36	Raab JR, Runge JS, Spear CC and Magnuson T: Co-regulation of transcription by BRG1 and BRM, two mutually exclusive SWI/SNF ATPase subunits. Epigenetics Chromatin. 10:622017. View Article : Google Scholar : PubMed/NCBI
37	Marquez SB, Thompson KW, Lu L and Reisman D: Beyond mutations: Additional mechanisms and implications of SWI/SNF complex inactivation. Front Oncol. 4:3722014.PubMed/NCBI
38	Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, Hahn WC and Roberts CWM: Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol. 34:1136–1144. 2014. View Article : Google Scholar : PubMed/NCBI
39	Yang T, Wang D, Tian G, Sun L, Yang M, Yin X, Xiao J, Sheng Y, Zhu D, He H and Zhou Y: Chromatin remodeling complexes regulate genome architecture in Arabidopsis. Plant Cell. 34:2638–2651. 2022. View Article : Google Scholar : PubMed/NCBI
40	Bowtell DD, Böhm S, Ahmed AA, Aspuria PJ, Bast RC Jr, Beral V, Berek JS, Birrer MJ, Blagden S, Bookman MA, et al: Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 15:668–679. 2015. View Article : Google Scholar : PubMed/NCBI
41	Zhang FL and Li DQ: Targeting chromatin-remodeling factors in cancer cells: Promising molecules in cancer therapy. Int J Mol Sci. 23:2022.
42	Wang J, Zhong F, Li J, Yue H, Li W and Lu X: The epigenetic factor CHD4 contributes to metastasis by regulating the EZH2/β-catenin axis and acts as a therapeutic target in ovarian cancer. J Transl Med. 21:382023. View Article : Google Scholar : PubMed/NCBI