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한국인의 폐선암 돌연변이 핫스팟: TP53 P72R Single Nucleotide Polymorphism의 발암성 돌연변이 가능성

Lung Adenocarcinoma Mutation Hotspot in Koreans: Oncogenic Mutation Potential of the TP53 P72R Single Nucleotide Polymorphism

Jae Ha BAEK|Kyu Bong CHO
대한임상검사과학회 (Korean Society for Clinical Laboratory Science)|2023.06|대한임상검사과학회지 (Korean Journal of Clinical Laboratory Science)|제55권 제2호|pp. 93-104|DOI 10.15324/kjcls.2023.55.2.93

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Lung cancerMutation hotspotTP53 P72R Single nucleotide polymorphism
주제분류기타자연과학

초록

이전 연구에서 83명의 한국인 폐선암 환자의 차세대 염기서열분석법(next generation sequencing, NGS) 분석 결과 돌연변이 빈도가 높은 상위 5개 유전자 TP53 (60%), EGFR (48%), KRAS (14%), PIK3CA (8%), CDKN2A (6%)를 확인했다. 본연구는NGS 분석을 이용하여 최근 한국인의 폐선암에서 돌연변이 발생빈도가 높은 상위 5개 유전자에 대한 돌연변이 핫스팟을 분석하여폐선암을 유발하는 새로운 표지자를 확인하고자 했으며 가장 많은돌연변이가 발생한 TP53 유전자의 돌연변이 유형과 패턴을 폐암의 주요 원인인 흡연과의 연관성을 분석했으며 TP53 P72R SNP 가 발생한 폐선암 환자의 임상병리학적 특성을 분석하고자 했다. TP53, EGFR, KRAS, PIK3CA, CDKN2A의 돌연변이 핫스팟을 분석한 결과 이전에 보고된 결과와 일치했으나 TP53의 경우 약간의 차이를 나타냈다. TP53 돌연변이 핫스팟은 DBD에집중하여 발생하는 점은 기존 연구 결과와 같았으나 코돈 72에서 발생하는 높은 돌연변이 빈도는 이전에 보고된 연구 결과와다르게 나타났다. TP53 돌연변이가 발생한 폐선암 환자의 임상특성을 분석한 결과 남성보다 여성, 흡연자보다 비흡연자에게더 많이 발생했다. 또한, TP53 돌연변이 유형은 흡연 여부와 상관없이 전환의 비율이 가장 높았으며 전환 또는 결실 그리고 전환과 결실이 동시에 발생하는 비율이 전이의 발생 비율보다 높게 나타났다. 한국인의 폐선암 증례에서 흡연 여부와 상관없이가장 발생 빈도가 높은 돌연변이 핫스팟은 TP53 코돈 72 뉴클레오타이드 염기가 C에서 G로의 전환되어 아미노산이 proline 에서 arginine으로 치환되는 TP53 P72R SNP 발생 비율이 가장 높게 나타났다. TP53 P72R SNP가 발생한 폐선암 증례들의임상병리학적 특성을 분석한 결과 환자의 연령, 성별, 흡연 유무그리고 종양의 분화도와 유의한 상관관계를 보이지 않았지만 낮은 병기와 유의한 상관관계를 나타냈다(P-value=0.026). 본연구는 NGS를 통해 한국인의 폐선암에서 돌연변이 발생빈도가 가장 많이 보고되었던 EGFR이 아닌 TP53의 증가를 확인했고 그중에서도 흡연 여부와 관계없이 TP53 P72R SNP의발생 빈도가 가장 높음을 보고하는 바이다.

Abstract

This study aimed to identify new markers that cause lung adenocarcinoma by analyzing mutation hotspots for the top five genes with high mutation frequency in lung adenocarcinoma in Koreans by next generation sequencing (NGS) analysis. The association between TP53 mutation types and patterns with smoking, a major cause of lung cancer, was examined. The clinicopathological characteristics of lung adenocarcinoma patients with TP53 P72R SNPs were analyzed. In Korean lung adenocarcinoma cases, regardless of the smoking status, the TP53 P72R SNP was the most frequently occurring mutational hotspot, in which the nucleotide base was transversed from C to G, and the amino acid was substituted from proline to arginine at codon 72 of TP53. An analysis of the clinicopathological characteristics of lung adenocarcinoma cases with TP53 P72R SNP revealed no significant correlation with the patient's age, gender, smoking status, and tumor differentiation, but a significant correlation with low stage (P -value =0.026). This study confirmed an increase in TP53 rather than EGFR, which was reported as the most frequent mutations in lung adenocarcinoma in Koreans through NGS. Among them, TP53 P72R SNP is the most frequent regardless of smoking status.

참고문헌 (40)

  1. Sung H, "Global cancer statistics 2020 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries", CA Cancer J Clin, 71, pp.209~249 (2021)[DOI]
  2. "Annual report of cancer statistics in Korea" (2019)[URL]
  3. "Global cancer data: GLOBOCAN 2018"[URL]
  4. "Lung Cancer Awareness Month 2022"[URL]
  5. Toufektchan E, "The guardian of the genome revisited : p53 downregulates genes required for telomere maintenance, DNA repair, and centromere structure", Cancers(Basel), 10, pp.135~ (2018)[DOI]
  6. Sabapathy K, "Therapeutic targeting of p53 : all mutants are equal, but some mutants are more equal than others", Nat Rev Clin Oncol, 15, pp.13~30 (2018)[DOI]
  7. Mogi A, "TP53 mutations in nonsmall cell lung cancer", J Biomed Biotechnol, 2011, pp.583929~ (2011)[DOI]
  8. Hecht SS, "Progress and challenges in selected areas of tobacco carcinogenesis", Chem Res Toxicol, 21, pp.160~171 (2008)[DOI]
  9. Bennett WP, "Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in never-smoking women", J Natl Cancer Inst, 91, pp.2009~2014 (1999)[DOI]
  10. Hainaut P, "Patterns of p53 G--＞T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke", Carcinogenesis, 22, pp.367~374 (2001)[DOI]
  11. Baugh EH, "Why are there hotspot mutations in the TP53 gene in human cancers?", Cell Death Differ, 25, pp.154~160 (2018)[DOI]
  12. Pfeifer GP, "Tobacco smoke carcinogens, DNA damage and p53mutations in smoking-associated cancers", Oncogene, 21, pp.7435~7451 (2002)[DOI]
  13. Hirsch FR, "Lung cancer : current therapies and new targeted treatments", Lancet, 389, pp.299~311 (2017)[DOI]
  14. Chan BA, "Targeted therapy for non-small cell lung cancer : current standards and the promise of the future", Transl Lung Cancer Res, 4, pp.36~54 (2015)[DOI]
  15. Al-Ahmadi A, "Next generation sequencing of advanced non-small cell lung cancer : utilization based on race and impact on survival", Clin Lung Cancer, 22, pp.16~22 (2021)[DOI]
  16. Jae Ha BAEK, "한국인의 폐선암 유전자 돌연변이: 차세대 염기서열 분석법을 이용한 검출 및 기존 유전자 검사법과의 일치도 분석", 대한임상검사과학회지, 55(1), pp.16~28 (2023), 대한임상검사과학회[DOI]
  17. Cancer Genome Atlas Research Network, "Comprehensive molecular profiling of lung adenocarcinoma", Nature, 514, pp.543~550 (2014)[DOI]
  18. Jiang R, "Validating a targeted next-generation sequencing assay and profiling somatic variants in Chinese non-small cell lung cancer patients", Sci Rep, 10, pp.2070~ (2020)[DOI]
  19. Kosaka T, "Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma", J Thorac Oncol, 4, pp.22~29 (2009)[DOI]
  20. Kenmotsu H, "Abstract 1537 : prospective mutational characterization of Japanese patients with non-small cell lung cancer by nextgeneration sequencing", Cancer Res, 74(Suppl 19), pp.1537~ (2014)[DOI]
  21. Chun YJ, "Molecular characterization of lung adenocarcinoma from Korean patients using next generation sequencing", PLoS One, 14, pp.e0224379~ (2019)[DOI]
  22. Shi Y, "A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology(PIONEER)", J Thorac Oncol, 9, pp.154~162 (2014)[DOI]
  23. Suda K, "EGFR T790M mutation : a double role in lung cancer cell survival?", J Thorac Oncol, 4, pp.1~4 (2009)[DOI]
  24. Riely GJ, "KRAS mutations in non-small cell lung cancer", Proc Am Thorac Soc, 6, pp.201~205 (2009)[DOI]
  25. Samuels Y, "Oncogenic mutations of PIK3CA in human cancers", Cell Cycle, 3, pp.1221~1224 (2004)[DOI]
  26. Kang S, "Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic", Proc Natl Acad Sci U S A, 102, pp.802~807 (2005)[DOI]
  27. Tam KW, "CDKN2A", p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer, 2013, pp.8, 1378~1388
  28. Larsen S, "LMO3 interacts with p53 and inhibits its transcriptional activity", Biochem Biophys Res Commun, 392, pp.252~257 (2010)[DOI]
  29. Levine AJ, "P53 and the defenses against genome instability caused by transposons and repetitive elements", Bioessays, 38, pp.508~513 (2016)[DOI]
  30. Wylie A, "p53genes function to restrain mobile elements", Genes Dev, 30, pp.64~77 (2016)[DOI]
  31. Kastan MB, "Participation of p53 protein in the cellular response to DNA damage", Cancer Res, 51(23 Pt 1), pp.6304~6311 (1991)
  32. Kastenhuber ER, "Putting p53 in context", Cell, 170, pp.1062~1078 (2017)[DOI]
  33. Nikulenkov F, "Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis", Cell Death Differ, 19, pp.1992~2002 (2012)[DOI]
  34. Thomas M, "Two polymorphic variants of wild-type p53 differ biochemically and biologically", Mol Cell Biol, 19, pp.1092~1100 (1999)[DOI]
  35. Boltze C, "Homozygous proline at codon 72 of p53 as a potential risk factor favoring the development of undifferentiated thyroid carcinoma", Int J Oncol, 21, pp.1151~1154 (2002)[DOI]
  36. Zhang C, "Gain-of-function mutant p53 in cancer progression and therapy", J Mol Cell Biol, 12, pp.674~687 (2020)[DOI]
  37. Alvarado-Ortiz E, "Mutant p53 gain-of-function : role in cancer development, progression, and therapeutic approaches", Front Cell Dev Biol, 8, pp.607670~ (2021)[DOI]
  38. Piao JM, "p53codon 72 polymorphism and the risk of lung cancer in a Korean population", Lung Cancer, 73, pp.264~267 (2011)[DOI]
  39. De Souza C, "Effect of the p53 P72R polymorphism on mutant TP53 allele selection in human cancer", J Natl Cancer Inst, 113, pp.1246~1257 (2021)[DOI]
  40. Risques RA, "Aging and the rise of somatic cancer-associated mutations in normal tissues", PLoS Genet, 14, pp.e1007108~ (2018)[DOI]

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