Genetic and Epigenetic Changes of CDKN2A in Gastric Cancer

Malik Ejder Yıldırım

doi:10.7197/cmj.1443256

Derleme

Genetic and Epigenetic Changes of CDKN2A in Gastric Cancer

Yıl 2024, , 99 - 103, 29.06.2024

Malik Ejder Yıldırım

https://doi.org/10.7197/cmj.1443256

Öz

Gastric cancer is a multifactorial heterogeneous disease involving various subgroups with different molecular features and it is one of the leading causes of cancer deaths worldwide. Although dietary conditions (fried, fatty and salty foods), tobacco and alcohol consumption, and some gastrointestinal infections are important in gastric cancer, the development of the disease is complex. It is clear that tumor suppressor genes and proto-oncogenes have a significant impact on the formation of gastric cancer. CDKN2A is a tumor suppressor gene that encodes two different proteins, and methylation, deletion and other mutations of this gene are effective in both the development and prognosis of gastric cancer. CDKN2A hypermethylation is common in gastric cancer related with H. Pylori and EBV infections. A connection is often established between metastases of gastric cancer and losses of this tumor suppressor gene (deletions). In this context, possible changes in the CDKN2A gene should be taken into consideration as a biomarker in the treatment and follow-up of gastric cancer.

Anahtar Kelimeler

Gastric cancer, tumor suppressor gene, CDKN2A, methylation, deletion

Teşekkür

Teşekkür ederim

Kaynakça

Bai S, Guo J, Zhang H. A meta-analysis of the clinicopathological significance of the lncRNA MALAT1 in human gastric cancer. Front Oncol. 2024;13:1257120.
Zheng HL, Wang FH, Zhang LK, Li P, Zheng CH, Chen QY, et al. Trajectories of neutrophil to lymphocyte ratios during neoadjuvant chemotherapy correlate with short- and long-term outcomes in gastric cancer: a group-based trajectory analysis. BMC Cancer. 2024;24(1):226.
Röcken C. J Predictive biomarkers in gastric cancer. Cancer Res Clin Oncol. 2023;149(1):467-81.
Smith MG, Hold GL, Tahara E, El-Omar EM. Cellular and molecular aspects of gastric cancer. World J Gastroenterol. 2006;12(19): 2979–90.
Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, PolkowskiWPGastriccancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239-48.
Chia NY, Tan P. Molecular classification of gastric cancer. Ann Oncol. 2016;27(5):763-9.
Correa P. Gastric cancer: overview. Gastroenterol Clin North Am. 2013;42(2):211-7.
Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.
Cheng XJ, Lin JC, Tu SP. Etiology and Prevention of Gastric Cancer. Gastrointest Tumors. 2016; 3(1): 25–36.
Petryszyn P, Chapelle N, Matysiak-Budnik T. Gastric Cancer: Where Are We Heading? Dig Dis. 2020;38(4):280-5.
Mukkamalla SKR, Recio-Boiles A, Babiker HM. Gastric Cancer. StatPearls Publishing; 2023. PMID: 29083746 Books & Documents.
Hui Y, Tu C, Liu D, Zhang H, Gong X. Risk factors for gastric cancer: A comprehensive analysis of observational studies. Front Public Health. 2023;10:892468.
Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, et al. Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC Genomics. 2015;16(Suppl 7):S8.
Zhu M, Zhu Z, Zhang N, Ma J, Huang N, He S, et al. Identification of miRNA, lncRNA and circRNA associated with gastric cancer metabolism through sequencing and bioinformatics analysis. Pathol Res Pract. 2024;254:155151.
Alves MK, Ferrasi AC, Lima VP, Ferreira MV, de Moura Campos Pardini MI, Rabenhorst SH. Inactivation of COX-2, HMLH1 and CDKN2A gene by promoter methylation in gastric cancer: relationship with histological subtype, tumor location and Helicobacter pylori genotype. Pathobiology. 2011;78(5):266-76.
Zhang J, Qiu W, Liu H, Qian C, Liu D, Wang H, et al. Genomic alterations in gastric cancers discovered via whole-exome sequencing. BMC Cancer. 2018;18(1):1270.
Shen Y, Shi K, Li D, Wang Q, Wu K, Feng C. Prognostic analysis of mutated genes and insight into effects of DNA damage and repair on mutational strand asymmetries in gastric cancer. Biochem Biophys Rep. 2023;37:101597.
Mahmud MT, Ahmed F, Rana MJ, Rahman MA, Atta A, Saif-Ur-Rahman KM. Association of HLA gene polymorphisms with Helicobacter pylori related gastric cancer-a systematic review. HLA. 2024;103(2):e15394.
Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cell Physiol Biochem. 2018;51(6):2647-93.
Tu Z, Wang X, Cai H, Sheng Y, Wu L, Huang K, et al. The cell senescence regulator p16 is a promising cancer prognostic and immune check-point inhibitor (ICI) therapy biomarker. Aging (Albany NY). 2023;15(6):2136-57.
Xu J, Li N, Deng W, Luo S. Discovering the mechanism and involvement of the methylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and its special locus region in gastric cancer. Bioengineered. 2021;12(1):1286-98.
Trietsch MD, Spaans VM, ter Haar NT, Osse EM, Peters AA, Gaarenstroom KN, et al. CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma. Gynecol Oncol. 2014;135(1):149-55.
Tang S, Luo H, Yu J, Yang D, Shu J. Relationship between alterations of p16(INK4a) and p14(ARF) genes of CDKN2A locus and gastric carcinogenesis. Chin Med J (Engl). 2003;116(7):1083-7.
Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50(25):5566-82.
Kowalczyk D, Nakasone MA, Smith BO, Huang DT. Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function. Life Sci Alliance. 2022;5(12):e202201472.
Fontana R, Ranieri M, La Mantia G, Vivo M. Dual Role of the Alternative Reading Frame ARF Protein in Cancer. Biomolecules. 2019;9(3):87.
Tu Q, Hao J, Zhou X, Yan L, Dai H, Sun B, et al. CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A. Oncogene. 2018;37(1):128-38.
Jiang Y, Wu Y, Zhang L, Wang Y, Xu G, Deng Y, et al. Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas. Precis Clin Med. 2023;6(4):pbad030.
Yang J, Liu Z, Zeng B, Hu G, Gan R. Epstein-Barr virus-associated gastric cancer: A distinct subtype. Cancer Lett. 2020;495:191-9.
Geddert H, Zur Hausen A, Gabbert HE, Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. Anal Cell Pathol (Amst). 2010;33(3):143-9.
Vo QN, Geradts J, Gulley ML, Boudreau DA, Bravo JC, Schneider BG. Epstein Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation. J Clin Pathol. 2002;55(9):669-75.
Kim TY, Jong HS, Jung Y, Kim TY, Kang GH, Bang YJ. DNA hypermethylation in gastric cancer. Aliment Pharmacol Ther. 2004;20 Suppl 1:131-42.
Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int J Clin Oncol. 2019;24(7):771-8.
Febres-Aldana CA, Chang JC, Jungbluth AA, Adusumilli PS, Bodd FM, Frosina D, et al. Comparison of immunohistochemistry, next generation sequencing and fluorescence in situ hybridization for detection of MTAP loss in pleural mesothelioma. Mod Pathol. 2024;37(3):100420.
Marshall K, Jackson S, Jones J, Holme J, Lyons J, Barrett E, et al. Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre. Lung Cancer. 2020;150:195-200.
Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS, et al. CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol. 2020;140(3):409-13.
Tillmanns N, Lost J, Tabor J, Vasandani S, Vetsa S, Marianayagam N, et al. Application of novel PACS-based informatics platform to identify imaging-based predictors of CDKN2A allelic status in glioblastomas. Sci Rep. 2023;13(1):22942.
Boşoteanu LA, Gheorghe E, Aşchie M, Cozaru GC, Deacu M, Orășanu CI, et al. Immunophenotypic p14 and p16 correlations with CDKN2A mutations in primary multiple and familial melanoma: An observational study. Medicine (Baltimore). 2023;102(51):e36756.
Kreuger IZM, Slieker RC, van Groningen T, van Doorn R. Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma. J Invest Dermatol. 2023;143(1):18-25.e1.
Tian Y, Zhou J, Qiao J, Liu Z, Gu L, Zhang B, et al. Detection of somatic copy number deletion of the CDKN2A gene by quantitative multiplex PCR for clinical practice. Front Oncol. 2022;12:1038380.
Yuile A, Satgunaseelan L, Wei JQ, Rodriguez M, Back M, Pavlakis N, et al. CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review. Curr Issues Mol Biol. 2023;45(7):5276-92.
Qiao J, Tian Y, Cheng X, Liu Z, Zhou J, Gu L, et al. CDKN2A Deletion Leading to Hematogenous Metastasis of Human Gastric Carcinoma. Front Oncol. 2021;11:801219.
Zhu J, Wang J, Liu H, Lei T, Yang J, Lan S, et al. Crosstalk of cuproptosis-related prognostic signature and competing endogenous RNAs regulation in hepatocellular carcinoma. Aging (Albany NY). 2023;15(23):13901-19.
Hosny G, Ahmed OA, Ahmed RM, Fadel SA. Expression of p16 Tumor SuppressorProtein in Malignant Ovarian Germ Cell Tumors; Immunohistochemical Study. Int J Surg Pathol. 2024;32(1):66-74.
Kishimoto I, Mitomi H, Ohkura Y, Kanazawa H, Fukui N, WatanabeM.Abnormalexpression of p16(INK4a), cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein in gastric carcinomas. J Surg Oncol. 2008;98(1):60-6.
Wang M, Zhao H, Chen W, Bie C, Yang J, Cai W, et al. The SMAD2/miR-4256/HDAC5/ p16INK4a signaling axis contributes to gastric cancer progression. Oncol Res. 2023;31(4):515-41.
Gulley ML. Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma. Exp Mol Med. 2015;47(1):e134.
Cheng Y, Bu D, Zhang Q, Sun R, Lyle S, Zhao G, et al. Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer. J Adv Res. 2023;51:121-34.

Gastrik Kanserde CDKN2A’nın Genetik ve Epigenetik Değişiklikleri

Yıl 2024, , 99 - 103, 29.06.2024

Malik Ejder Yıldırım

https://doi.org/10.7197/cmj.1443256

Öz

Mide kanseri, farklı moleküler özelliklere sahip çeşitli alt grupları içeren multifaktöriyel, heterojen bir hastalıktır ve dünya çapında kanser ölümlerinin önde gelen nedenlerinden biridir. Gastrik kanserde beslenme koşulları (kızarmış, yağlı ve tuzlu yiyecekler), tütün ve alkol tüketimi ve bazı gastrointestinal enfeksiyonlar önemli olmasına rağmen hastalığın gelişimi karmaşıktır. Tümör baskılayıcı genlerin ve proto-onkogenlerin mide kanserinin oluşumunda önemli bir etkiye sahip olduğu açıktır. CDKN2A, iki farklı proteini kodlayan tümör supresör bir gendir ve bu genin metilasyonu, delesyonu ve diğer mutasyonları mide kanserinin hem gelişiminde hem de prognozunda etkilidir. CDKN2A hipermetilasyonu, H. Pylori ve EBV enfeksiyonlarıyla ilişkili mide kanserinde yaygındır. Mide kanserinin metastazları ile bu tümör baskılayıcı genin kayıpları (delesyonlar) arasında sıklıkla bir bağlantı kurulmaktadır. Bu bağlamda, mide kanserinin tedavi ve takibinde biyobelirteç olarak CDKN2A genindeki olası değişiklikler göz önüne alınmalıdır.

Anahtar Kelimeler

Mide kanseri, tümör supresör gen, CDKN2A, metilasyon, delesyon

Kaynakça

Bai S, Guo J, Zhang H. A meta-analysis of the clinicopathological significance of the lncRNA MALAT1 in human gastric cancer. Front Oncol. 2024;13:1257120.
Zheng HL, Wang FH, Zhang LK, Li P, Zheng CH, Chen QY, et al. Trajectories of neutrophil to lymphocyte ratios during neoadjuvant chemotherapy correlate with short- and long-term outcomes in gastric cancer: a group-based trajectory analysis. BMC Cancer. 2024;24(1):226.
Röcken C. J Predictive biomarkers in gastric cancer. Cancer Res Clin Oncol. 2023;149(1):467-81.
Smith MG, Hold GL, Tahara E, El-Omar EM. Cellular and molecular aspects of gastric cancer. World J Gastroenterol. 2006;12(19): 2979–90.
Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, PolkowskiWPGastriccancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239-48.
Chia NY, Tan P. Molecular classification of gastric cancer. Ann Oncol. 2016;27(5):763-9.
Correa P. Gastric cancer: overview. Gastroenterol Clin North Am. 2013;42(2):211-7.
Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.
Cheng XJ, Lin JC, Tu SP. Etiology and Prevention of Gastric Cancer. Gastrointest Tumors. 2016; 3(1): 25–36.
Petryszyn P, Chapelle N, Matysiak-Budnik T. Gastric Cancer: Where Are We Heading? Dig Dis. 2020;38(4):280-5.
Mukkamalla SKR, Recio-Boiles A, Babiker HM. Gastric Cancer. StatPearls Publishing; 2023. PMID: 29083746 Books & Documents.
Hui Y, Tu C, Liu D, Zhang H, Gong X. Risk factors for gastric cancer: A comprehensive analysis of observational studies. Front Public Health. 2023;10:892468.
Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, et al. Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC Genomics. 2015;16(Suppl 7):S8.
Zhu M, Zhu Z, Zhang N, Ma J, Huang N, He S, et al. Identification of miRNA, lncRNA and circRNA associated with gastric cancer metabolism through sequencing and bioinformatics analysis. Pathol Res Pract. 2024;254:155151.
Alves MK, Ferrasi AC, Lima VP, Ferreira MV, de Moura Campos Pardini MI, Rabenhorst SH. Inactivation of COX-2, HMLH1 and CDKN2A gene by promoter methylation in gastric cancer: relationship with histological subtype, tumor location and Helicobacter pylori genotype. Pathobiology. 2011;78(5):266-76.
Zhang J, Qiu W, Liu H, Qian C, Liu D, Wang H, et al. Genomic alterations in gastric cancers discovered via whole-exome sequencing. BMC Cancer. 2018;18(1):1270.
Shen Y, Shi K, Li D, Wang Q, Wu K, Feng C. Prognostic analysis of mutated genes and insight into effects of DNA damage and repair on mutational strand asymmetries in gastric cancer. Biochem Biophys Rep. 2023;37:101597.
Mahmud MT, Ahmed F, Rana MJ, Rahman MA, Atta A, Saif-Ur-Rahman KM. Association of HLA gene polymorphisms with Helicobacter pylori related gastric cancer-a systematic review. HLA. 2024;103(2):e15394.
Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cell Physiol Biochem. 2018;51(6):2647-93.
Tu Z, Wang X, Cai H, Sheng Y, Wu L, Huang K, et al. The cell senescence regulator p16 is a promising cancer prognostic and immune check-point inhibitor (ICI) therapy biomarker. Aging (Albany NY). 2023;15(6):2136-57.
Xu J, Li N, Deng W, Luo S. Discovering the mechanism and involvement of the methylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and its special locus region in gastric cancer. Bioengineered. 2021;12(1):1286-98.
Trietsch MD, Spaans VM, ter Haar NT, Osse EM, Peters AA, Gaarenstroom KN, et al. CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma. Gynecol Oncol. 2014;135(1):149-55.
Tang S, Luo H, Yu J, Yang D, Shu J. Relationship between alterations of p16(INK4a) and p14(ARF) genes of CDKN2A locus and gastric carcinogenesis. Chin Med J (Engl). 2003;116(7):1083-7.
Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50(25):5566-82.
Kowalczyk D, Nakasone MA, Smith BO, Huang DT. Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function. Life Sci Alliance. 2022;5(12):e202201472.
Fontana R, Ranieri M, La Mantia G, Vivo M. Dual Role of the Alternative Reading Frame ARF Protein in Cancer. Biomolecules. 2019;9(3):87.
Tu Q, Hao J, Zhou X, Yan L, Dai H, Sun B, et al. CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A. Oncogene. 2018;37(1):128-38.
Jiang Y, Wu Y, Zhang L, Wang Y, Xu G, Deng Y, et al. Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas. Precis Clin Med. 2023;6(4):pbad030.
Yang J, Liu Z, Zeng B, Hu G, Gan R. Epstein-Barr virus-associated gastric cancer: A distinct subtype. Cancer Lett. 2020;495:191-9.
Geddert H, Zur Hausen A, Gabbert HE, Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. Anal Cell Pathol (Amst). 2010;33(3):143-9.
Vo QN, Geradts J, Gulley ML, Boudreau DA, Bravo JC, Schneider BG. Epstein Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation. J Clin Pathol. 2002;55(9):669-75.
Kim TY, Jong HS, Jung Y, Kim TY, Kang GH, Bang YJ. DNA hypermethylation in gastric cancer. Aliment Pharmacol Ther. 2004;20 Suppl 1:131-42.
Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int J Clin Oncol. 2019;24(7):771-8.
Febres-Aldana CA, Chang JC, Jungbluth AA, Adusumilli PS, Bodd FM, Frosina D, et al. Comparison of immunohistochemistry, next generation sequencing and fluorescence in situ hybridization for detection of MTAP loss in pleural mesothelioma. Mod Pathol. 2024;37(3):100420.
Marshall K, Jackson S, Jones J, Holme J, Lyons J, Barrett E, et al. Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre. Lung Cancer. 2020;150:195-200.
Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS, et al. CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol. 2020;140(3):409-13.
Tillmanns N, Lost J, Tabor J, Vasandani S, Vetsa S, Marianayagam N, et al. Application of novel PACS-based informatics platform to identify imaging-based predictors of CDKN2A allelic status in glioblastomas. Sci Rep. 2023;13(1):22942.
Boşoteanu LA, Gheorghe E, Aşchie M, Cozaru GC, Deacu M, Orășanu CI, et al. Immunophenotypic p14 and p16 correlations with CDKN2A mutations in primary multiple and familial melanoma: An observational study. Medicine (Baltimore). 2023;102(51):e36756.
Kreuger IZM, Slieker RC, van Groningen T, van Doorn R. Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma. J Invest Dermatol. 2023;143(1):18-25.e1.
Tian Y, Zhou J, Qiao J, Liu Z, Gu L, Zhang B, et al. Detection of somatic copy number deletion of the CDKN2A gene by quantitative multiplex PCR for clinical practice. Front Oncol. 2022;12:1038380.
Yuile A, Satgunaseelan L, Wei JQ, Rodriguez M, Back M, Pavlakis N, et al. CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review. Curr Issues Mol Biol. 2023;45(7):5276-92.
Qiao J, Tian Y, Cheng X, Liu Z, Zhou J, Gu L, et al. CDKN2A Deletion Leading to Hematogenous Metastasis of Human Gastric Carcinoma. Front Oncol. 2021;11:801219.
Zhu J, Wang J, Liu H, Lei T, Yang J, Lan S, et al. Crosstalk of cuproptosis-related prognostic signature and competing endogenous RNAs regulation in hepatocellular carcinoma. Aging (Albany NY). 2023;15(23):13901-19.
Hosny G, Ahmed OA, Ahmed RM, Fadel SA. Expression of p16 Tumor SuppressorProtein in Malignant Ovarian Germ Cell Tumors; Immunohistochemical Study. Int J Surg Pathol. 2024;32(1):66-74.
Kishimoto I, Mitomi H, Ohkura Y, Kanazawa H, Fukui N, WatanabeM.Abnormalexpression of p16(INK4a), cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein in gastric carcinomas. J Surg Oncol. 2008;98(1):60-6.
Wang M, Zhao H, Chen W, Bie C, Yang J, Cai W, et al. The SMAD2/miR-4256/HDAC5/ p16INK4a signaling axis contributes to gastric cancer progression. Oncol Res. 2023;31(4):515-41.
Gulley ML. Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma. Exp Mol Med. 2015;47(1):e134.
Cheng Y, Bu D, Zhang Q, Sun R, Lyle S, Zhao G, et al. Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer. J Adv Res. 2023;51:121-34.

Toplam 48 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	İngilizce
Konular	Multimorbidite
Bölüm	Derlemeler
Yazarlar	Malik Ejder Yıldırım 0000-0003-4386-1583
Yayımlanma Tarihi	29 Haziran 2024
Gönderilme Tarihi	26 Şubat 2024
Kabul Tarihi	22 Nisan 2024
Yayımlandığı Sayı	Yıl 2024

Kaynak Göster

AMA	Yıldırım ME. Genetic and Epigenetic Changes of CDKN2A in Gastric Cancer. CMJ. Haziran 2024;46(2):99-103. doi:10.7197/cmj.1443256

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