Increased Copy Number of Imprinted Genes in the Chromosomal Region 20q11-q13.32 is Associated with Resistance to Antitumor Agents in Cancer Cell Lines

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2022 Dec 2

PMID 36461044

Authors

Julia Krushkal

Suleyman Vural

Travis L Jensen

George Wright

Yingdong Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment.

Results: We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes.

Conclusions: Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy.

References

Kim J, Bretz C, Lee S . Epigenetic instability of imprinted genes in human cancers. Nucleic Acids Res. 2015; 43(22):10689-99. PMC: 4678850. DOI: 10.1093/nar/gkv867. View

Romanet P, Galluso J, Kamenicky P, Hage M, Theodoropoulou M, Roche C . Somatotroph Tumors and the Epigenetic Status of the Locus. Int J Mol Sci. 2021; 22(14). PMC: 8306130. DOI: 10.3390/ijms22147570. View

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

Bottomly D, Long N, Schultz A, Kurtz S, Tognon C, Johnson K . Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. Cancer Cell. 2022; 40(8):850-864.e9. PMC: 9378589. DOI: 10.1016/j.ccell.2022.07.002. View

Zhou J, Cheng T, Li X, Hu J, Li E, Ding M . Epigenetic imprinting alterations as effective diagnostic biomarkers for early-stage lung cancer and small pulmonary nodules. Clin Epigenetics. 2021; 13(1):220. PMC: 8672623. DOI: 10.1186/s13148-021-01203-5. View

Bar-Shira A, Pinthus J, Rozovsky U, Goldstein M, Sellers W, Yaron Y . Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. Cancer Res. 2002; 62(23):6803-7. View

Rezvani G, Lui J, Barnes K, Baron J . A set of imprinted genes required for normal body growth also promotes growth of rhabdomyosarcoma cells. Pediatr Res. 2012; 71(1):32-8. PMC: 3420822. DOI: 10.1038/pr.2011.6. View

Wawrzik M, Spiess A, Herrmann R, Buiting K, Horsthemke B . Expression of SNURF-SNRPN upstream transcripts and epigenetic regulatory genes during human spermatogenesis. Eur J Hum Genet. 2009; 17(11):1463-70. PMC: 2986690. DOI: 10.1038/ejhg.2009.83. View

Kayashima T, Yamasaki K, Yamada T, Sakai H, Miwa N, Ohta T . The novel imprinted carboxypeptidase A4 gene ( CPA4) in the 7q32 imprinting domain. Hum Genet. 2003; 112(3):220-6. DOI: 10.1007/s00439-002-0891-3. View

10.

Imataki O, Ishida T, Kubo H, Uemura M, Nanya Y, Kawakami K . A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation. Case Rep Oncol. 2020; 13(1):449-455. PMC: 7204851. DOI: 10.1159/000506452. View

11.

Feng X, Song Z, Huang Q, Jia J, Zhang L, Zhu M . AIM2 Promotes Gastric Cancer Cell Proliferation via the MAPK Signaling Pathway. J Healthc Eng. 2022; 2022:8756844. PMC: 9010154. DOI: 10.1155/2022/8756844. View

12.

Greife A, Knievel J, Ribarska T, Niegisch G, Schulz W . Concomitant downregulation of the imprinted genes DLK1 and MEG3 at 14q32.2 by epigenetic mechanisms in urothelial carcinoma. Clin Epigenetics. 2015; 6(1):29. PMC: 4348104. DOI: 10.1186/1868-7083-6-29. View

13.

Cuellar Partida G, Laurin C, Ring S, Gaunt T, McRae A, Visscher P . Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans. Hum Mol Genet. 2018; 27(16):2927-2939. PMC: 6077796. DOI: 10.1093/hmg/ddy206. View

14.

Zhang S, Lovejoy K, Shima J, Lagpacan L, Shu Y, Lapuk A . Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006; 66(17):8847-57. PMC: 2775093. DOI: 10.1158/0008-5472.CAN-06-0769. View

15.

Adkins R, Krushkal J, Magann E, Klauser C, Morrison J, Ramsey R . Association of maternally inherited GNAS alleles with African-American male birth weight. Int J Pediatr Obes. 2009; 5(2):177-84. PMC: 2928065. DOI: 10.3109/17477160903111714. View

16.

Babak T, Deveale B, Tsang E, Zhou Y, Li X, Smith K . Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat Genet. 2015; 47(5):544-9. PMC: 4414907. DOI: 10.1038/ng.3274. View

17.

Patel V, Szasz I, Koroknai V, Kiss T, Balazs M . Molecular Alterations Associated with Acquired Drug Resistance during Combined Treatment with Encorafenib and Binimetinib in Melanoma Cell Lines. Cancers (Basel). 2021; 13(23). PMC: 8656772. DOI: 10.3390/cancers13236058. View

18.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

19.

Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C . Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell. 2006; 11(5):711-22. DOI: 10.1016/j.devcel.2006.09.003. View

20.

Mantovani G, Lania A, Spada A . GNAS imprinting and pituitary tumors. Mol Cell Endocrinol. 2010; 326(1-2):15-8. DOI: 10.1016/j.mce.2010.04.009. View