Study on the single nucleotide polymorphism and genes with copy number variation of cardiac myxoma_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

FAN Jidan , XIE Yufeng , YAN Daliang , WANG Kaihang ,  ZHU Pengcheng

Department of Cardiovascular Surgery, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, P. R. China;

Corresponding author：

ZHU Pengcheng, Email: clinicalzhupc@163.com

Keywords：

Cardiac myxoma; whole genome sequencing; single nucleotide polymorphism; copy number variation

DOI：

10.7507/1007-4848.202308012

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To analyze the single nucleotide polymorphism (SNP) and the copy number variation (CNV) of cardiac tumors to find the SNP sites and CNV events that may play important roles in the occurrence of tumors. Methods The patients with myxoma admitted to our hospital from 2015 to 2019 were randomly selected. The SNP analysis and the CNV test in gene level were performed through whole exome sequencing (WES). The samples were divided into two groups according to the mean size of the tumor: a diameter≤5.7 cm group and a dimeter>5.7 cm group. The analysis results were compared between the two groups. Results A total of 14 patients were enrolled, including 8 females and 6 males with a mean age of 61.4 (41-79) years. Thirty-seven cancer-genes with SNP were detected, among which 18 mutated sites had a mutation rate of>10%; and TP53, EP300 and CREBBP played a core binding role in protein-protein interaction-network. The GO enrichment results showed significant differences in the regulation of cell secretion of the mutated genes, and the KEGG enrichment results showed significant differences in the PI3K-AKT and JAK-STAT signaling pathways in the occurrence of myxoma. In addition, 17 new mutation sites of tumor genes with high mutation effect were found in SNP detection. The WES results of 14 samples showed that the CNV events were detected in 120 tumor genes of the samples, 10 of which were included in two tumor databases. The GO enrichment results showed significant differences in the tube development and regulation of cell proliferation, and the KEGG enrichment results showed significant differences in the comprehensive tumor signaling pathway. Statistical differences of ERCC6L and INTS6L in CNV test were found (P<0.05). Conclusion There may be multiple tumor gene site mutations in the process of tumor generation, among which there are multiple core tumor genes such as TP53, EP300 and CREB, which regulate tumor cells through PI3K-AKT and JAK-STAT signaling pathways and play an important role in tumor generation. The CNV of ERCC6L and INTS6L genes may be related to tumor growth.

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8.	Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics, 2009, 25(16): 2078-2079.
9.	McKenna A, Hanna M, Banks E, et al. The genome analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res, 2010, 20(9): 1297-1303.
10.	Lai Z, Markovets A, Ahdesmaki M, et al. VarDict: A novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res, 2016, 44(11): e108.
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12.	Talevich E, Shain AH, Botton T, et al. CNVkit: Genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput Biol, 2016, 12(4): e1004873.
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15.	Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature, 2012, 486(7403): 400-404.
16.	Shao F, Guo T, Chua PJ, et al. Clinicopathological significance of ARID1B in breast invasive ductal carcinoma. Histopathology, 2015, 67(5): 709-718.
17.	Zou Y, Zheng S, Xie X, et al. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun, 2022, 13(1): 2672.
18.	Xie M, Lin Z, Ji X, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol, 2023, 79(1): 109-125.
19.	Levine KM, Ding K, Chen L, et al. FGFR4: A promising therapeutic target for breast cancer and other solid tumors. Pharmacol Ther, 2020, 214: 107590.
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22.	Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat, 2018, 167(2): 417-423.
23.	Silwal-Pandit L, Langerød A, Børresen-Dale AL. Tp53 mutations in breast and ovarian cancer. Cold Spring Harb Perspect Med. 2017, 7(1): a026252.
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25.	Lui WO, Zeng L, Rehrmann V, et al. CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Res, 2008, 68(17): 7156-7164.
26.	Panagopoulos I, Möller E, Dahlén A, et al. Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera. Genes Chromosomes Cancer, 2007, 46(2): 181-191.
27.	Martinez GJ, Pereira RM, Äijö T, et al. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity, 2015, 42(2): 265-278.
28.	Chen Z, Soutto M, Rahman B, et al. Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia. Genes Chromosomes Cancer, 2017, 56(7): 535-547.
29.	Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature, 2017, 543(7647): 733-737.
30.	Graham RP, Lackner C, Terracciano L, et al. Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology, 2018, 68(4): 1441-1447.
31.	Wang S, Cheng Y, Zheng Y, et al. PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma. Sci Rep, 2016, 6: 39630.
32.	Ma S, Liu W, Zhang A, et al. Identification of a PRKAR1A mutation (c. 491_492delTG) in familial cardiac myxoma: A case report. Medicine (Baltimore), 2019, 98(11): e14866.
33.	He J, Sun M, Li E, et al. Recurrent somatic mutations of PRKAR1A in isolated cardiac myxoma. Oncotarget, 2017, 8(61): 103968-103974.
34.	Gu X, Xue J, Ai L, et al. SND1 expression in breast cancer tumors is associated with poor prognosis. Ann N Y Acad Sci, 2018, 1433(1): 53-60.
35.	Cui X, Zhao C, Yao X, et al. SND1 acts as an anti-apoptotic factor via regulating the expression of lncRNA UCA1 in hepatocellular carcinoma. RNA Biol, 2018, 15(10): 1364-1375.
36.	Blees A, Januliene D, Hofmann T, et al. Structure of the human MHC-Ⅰ peptide-loading complex. Nature, 2017, 551(7681): 525-528.
37.	Ling A, Löfgren-Burström A, Larsson P, et al. TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. Oncoimmunology, 2017, 6(11): e1356143.
38.	Sultan M, Vidovic D, Paine AS, et al. Epigenetic silencing of TAP1 in Aldefluor+ breast cancer stem cells contributes to their enhanced immune evasion. Stem Cells, 2018, 36(5): 641-654.
39.	Matassa DS, Amoroso MR, Lu H, et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ, 2016, 23(9): 1542-1554.
40.	Berry JL, Polski A, Cavenee WK, et al. The rb1 story: Characterization and cloning of the first tumor suppressor gene. Genes (Basel), 2019, 10(11): 879.
41.	Zhou Y, Wu C, Lu G, et al. FGF/FGFR signaling pathway involved resistance in various cancer types. J Cancer, 2020, 11(8): 2000-2007.
42.	Derakhshan I. Comments on "Sugawara, K. , & Kasai, T. (2002). Facilitation of motor evoked potentials and H-reflexes of flexor carpi radialis muscle induced by voluntary teeth clinching. Human Movement Science, 21, 203-212". Hum Mov Sci, 2003, 22(1): 125-127.
43.	Valverde AM, González-Rodríguez A. IRS2 and PTP1B: Two opposite modulators of hepatic insulin signalling. Arch Physiol Biochem, 2011, 117(3): 105-115.
44.	Kung WH, Yu CF, Lee AC, et al. Gene expression profiling of tumor-associated macrophages after exposure to single-dose irradiation. Comput Biol Chem, 2017, 69: 138-146.
45.	Adefuye A, Sales K. Regulation of inflammatory pathways in cancer and infectious disease of the cervix. Scientifica (Cairo), 2012, 2012: 548150.
46.	Nakamura Y, Kita S, Tanaka Y, et al. A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol, 2020, 318(2): H238-H251.
47.	Du Q, Wang W, Liu T, et al. High expression of integrin α3 predicts poor prognosis and promotes tumor metastasis and angiogenesis by activating the c-Src/extracellular signal-regulated protein kinase/focal adhesion kinase signaling pathway in cervical cancer. Front Oncol, 2020, 10: 36.

1. Barreiro M, Renilla A, Jimenez JM, et al. Primary cardiac tumors: 32 years of experience from a Spanish tertiary surgical center. Cardiovasc Pathol, 2013, 22(6): 424-427.
2. Yuan SM. Mitral valve myxoma: Clinical features, current diagnostic approaches, and surgical management. Cardiol J, 2012, 19(1): 105-109.
3. Gošev I, Paić F, Durić Z, et al. Cardiac myxoma the great imitators: comprehensive histopathological and molecular approach. Int J Cardiol, 2013, 164(1): 7-20.
4. 胡盛寿, 王小啟, 许建屏, 等. 心脏肿瘤外科治疗经验总结. 中华医学杂志, 2006, 86(11): 766-770.
5. Presta I, Donato A, Chirchiglia D, et al. Cardiac myxoma and neural crests: A tense relationship. Cardiovasc Pathol, 2020, 44: 107163.
6. Chen S, Zhou Y, Chen Y, et al. Fastp: An ultra-fast all-in-one fastq preprocessor. Bioinformatics, 2018, 34(17): i884-i890.
7. García-Alcalde F, Okonechnikov K, Carbonell J, et al. Qualimap: Evaluating next-generation sequencing alignment data. Bioinformatics, 2012, 28(20): 2678-2679.
8. Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics, 2009, 25(16): 2078-2079.
9. McKenna A, Hanna M, Banks E, et al. The genome analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res, 2010, 20(9): 1297-1303.
10. Lai Z, Markovets A, Ahdesmaki M, et al. VarDict: A novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res, 2016, 44(11): e108.
11. Yu G, Wang LG, Han Y, et al. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
12. Talevich E, Shain AH, Botton T, et al. CNVkit: Genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput Biol, 2016, 12(4): e1004873.
13. Ishizaki Y, Ikeda S, Fujimori M, et al. Immunohistochemical analysis and mutational analyses of beta-catenin, axin family and apc genes in hepatocellular carcinomas. Int J Oncol, 2004, 24(5): 1077-1083.
14. Helming KC, Wang X, Wilson BG, et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med, 2014, 20(3): 251-254.
15. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature, 2012, 486(7403): 400-404.
16. Shao F, Guo T, Chua PJ, et al. Clinicopathological significance of ARID1B in breast invasive ductal carcinoma. Histopathology, 2015, 67(5): 709-718.
17. Zou Y, Zheng S, Xie X, et al. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun, 2022, 13(1): 2672.
18. Xie M, Lin Z, Ji X, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol, 2023, 79(1): 109-125.
19. Levine KM, Ding K, Chen L, et al. FGFR4: A promising therapeutic target for breast cancer and other solid tumors. Pharmacol Ther, 2020, 214: 107590.
20. Li YY, Tian T, Zhang R, et al. Association between polymorphism of GLI1 gene SNP rs2228226 and chronic lymphocytic leukemia in Chinese population. Med Oncol, 2014, 31(12): 294.
21. Giacomelli AO, Yang X, Lintner RE, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet, 2018, 50(10): 1381-1387.
22. Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat, 2018, 167(2): 417-423.
23. Silwal-Pandit L, Langerød A, Børresen-Dale AL. Tp53 mutations in breast and ovarian cancer. Cold Spring Harb Perspect Med. 2017, 7(1): a026252.
24. Öner MG, Rokavec M, Kaller M, et al. Combined inactivation of TP53 and MIR34A promotes colorectal cancer development and progression in mice via increasing levels of IL6R and PAI1. Gastroenterology, 2018, 155(6): 1868-1882.
25. Lui WO, Zeng L, Rehrmann V, et al. CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Res, 2008, 68(17): 7156-7164.
26. Panagopoulos I, Möller E, Dahlén A, et al. Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera. Genes Chromosomes Cancer, 2007, 46(2): 181-191.
27. Martinez GJ, Pereira RM, Äijö T, et al. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity, 2015, 42(2): 265-278.
28. Chen Z, Soutto M, Rahman B, et al. Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia. Genes Chromosomes Cancer, 2017, 56(7): 535-547.
29. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature, 2017, 543(7647): 733-737.
30. Graham RP, Lackner C, Terracciano L, et al. Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology, 2018, 68(4): 1441-1447.
31. Wang S, Cheng Y, Zheng Y, et al. PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma. Sci Rep, 2016, 6: 39630.
32. Ma S, Liu W, Zhang A, et al. Identification of a PRKAR1A mutation (c. 491_492delTG) in familial cardiac myxoma: A case report. Medicine (Baltimore), 2019, 98(11): e14866.
33. He J, Sun M, Li E, et al. Recurrent somatic mutations of PRKAR1A in isolated cardiac myxoma. Oncotarget, 2017, 8(61): 103968-103974.
34. Gu X, Xue J, Ai L, et al. SND1 expression in breast cancer tumors is associated with poor prognosis. Ann N Y Acad Sci, 2018, 1433(1): 53-60.
35. Cui X, Zhao C, Yao X, et al. SND1 acts as an anti-apoptotic factor via regulating the expression of lncRNA UCA1 in hepatocellular carcinoma. RNA Biol, 2018, 15(10): 1364-1375.
36. Blees A, Januliene D, Hofmann T, et al. Structure of the human MHC-Ⅰ peptide-loading complex. Nature, 2017, 551(7681): 525-528.
37. Ling A, Löfgren-Burström A, Larsson P, et al. TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. Oncoimmunology, 2017, 6(11): e1356143.
38. Sultan M, Vidovic D, Paine AS, et al. Epigenetic silencing of TAP1 in Aldefluor+ breast cancer stem cells contributes to their enhanced immune evasion. Stem Cells, 2018, 36(5): 641-654.
39. Matassa DS, Amoroso MR, Lu H, et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ, 2016, 23(9): 1542-1554.
40. Berry JL, Polski A, Cavenee WK, et al. The rb1 story: Characterization and cloning of the first tumor suppressor gene. Genes (Basel), 2019, 10(11): 879.
41. Zhou Y, Wu C, Lu G, et al. FGF/FGFR signaling pathway involved resistance in various cancer types. J Cancer, 2020, 11(8): 2000-2007.
42. Derakhshan I. Comments on "Sugawara, K. , & Kasai, T. (2002). Facilitation of motor evoked potentials and H-reflexes of flexor carpi radialis muscle induced by voluntary teeth clinching. Human Movement Science, 21, 203-212". Hum Mov Sci, 2003, 22(1): 125-127.
43. Valverde AM, González-Rodríguez A. IRS2 and PTP1B: Two opposite modulators of hepatic insulin signalling. Arch Physiol Biochem, 2011, 117(3): 105-115.
44. Kung WH, Yu CF, Lee AC, et al. Gene expression profiling of tumor-associated macrophages after exposure to single-dose irradiation. Comput Biol Chem, 2017, 69: 138-146.
45. Adefuye A, Sales K. Regulation of inflammatory pathways in cancer and infectious disease of the cervix. Scientifica (Cairo), 2012, 2012: 548150.
46. Nakamura Y, Kita S, Tanaka Y, et al. A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol, 2020, 318(2): H238-H251.
47. Du Q, Wang W, Liu T, et al. High expression of integrin α3 predicts poor prognosis and promotes tumor metastasis and angiogenesis by activating the c-Src/extracellular signal-regulated protein kinase/focal adhesion kinase signaling pathway in cervical cancer. Front Oncol, 2020, 10: 36.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Latest ArticlesStudy on the single nucleotide polymorphism and genes with copy number variation of cardiac myxoma

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