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Соматические мутации при колоректальном раке: опыт региона
Соматические мутации при колоректальном раке: опыт региона
Огнерубов Н.А., Ежова Е.Н. Соматические мутации при колоректальном раке: опыт региона. Consilium Medicum. 2022;24(5):291–296. DOI: 10.26442/20751753.2022.5.201796
© ООО «КОНСИЛИУМ МЕДИКУМ», 2022 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2022 г.
________________________________________________
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Введение. Колоректальный рак является одним из самых распространенных злокачественных новообразований в экономически развитых странах мира, занимает 3 и 2-е место в структуре заболеваемости и смертности. Современные знания о молекулярной характеристике колоректального рака необходимы для реализации принципа персонализированной терапии.
Цель. Изучить региональные особенности геномного ландшафта опухоли при колоректальном раке.
Материалы и методы. В ретроспективное исследование с 2019 по 2022 г. включены 153 пациента с I–IV стадией колоректального рака в возрасте от 32 до 80 лет, медиана – 63,8 года. Исследования проведены на образцах ДНК, выделенной из парафиновых блоков опухолевой ткани методом полимеразной цепной реакции в режиме реального времени. Мужчин – 43,8%, женщин – 56,2%.
Результаты. Соматические мутации выявлены у 48,4% пациентов. Максимальное количество мутаций выявлено в гене KRAS – 60 (81%). Частота достоверно выше у женщин относительно мужчин. Мутации KRAS преобладают в ободочной кишке по сравнению с прямой, составляя 66,7 и 33,3% соответственно. В опухолях правой половины ободочной кишки эти мутации выявлены в 18,3% случаев, а в левой – у 48,4%. Мутации NRAS обнаружены в 9,5% наблюдений, в основном при опухолях левой половины ободочной кишки. Мутации BRAF диагностированы у 6 больных, причем женщин среди них – 5, а опухоли локализовались в правой половине кишки. Наибольшая частота мутаций KRAS наблюдалась в 12 и 13-м кодонах, составляя 86,7%. У большинства больных встречалась мутация G12V – 25%, за ней следовали G12D – 20% и G12A – 16,6%.
Заключение. Соматические мутации в генах семейства RAS и BRAF при колоректальном раке в Тамбовской области выявлены в 48,4% наблюдений. Среди них отмечается превалирование мутаций KRAS – 81% у лиц женского пола. Онкогенные мутации KRAS являются предикторами ответа на лечение и прогноз.
Ключевые слова: колоректальный рак, соматические мутации, NRAS, KRAS, BRAF
Aim. To study regional features of tumor genomic landscape in colorectal cancer.
Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage I–IV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females.
Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene – 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%).
Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations – 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.
Keywords: colorectal cancer, somatic mutations, NRAS, KRAS, BRAF
Цель. Изучить региональные особенности геномного ландшафта опухоли при колоректальном раке.
Материалы и методы. В ретроспективное исследование с 2019 по 2022 г. включены 153 пациента с I–IV стадией колоректального рака в возрасте от 32 до 80 лет, медиана – 63,8 года. Исследования проведены на образцах ДНК, выделенной из парафиновых блоков опухолевой ткани методом полимеразной цепной реакции в режиме реального времени. Мужчин – 43,8%, женщин – 56,2%.
Результаты. Соматические мутации выявлены у 48,4% пациентов. Максимальное количество мутаций выявлено в гене KRAS – 60 (81%). Частота достоверно выше у женщин относительно мужчин. Мутации KRAS преобладают в ободочной кишке по сравнению с прямой, составляя 66,7 и 33,3% соответственно. В опухолях правой половины ободочной кишки эти мутации выявлены в 18,3% случаев, а в левой – у 48,4%. Мутации NRAS обнаружены в 9,5% наблюдений, в основном при опухолях левой половины ободочной кишки. Мутации BRAF диагностированы у 6 больных, причем женщин среди них – 5, а опухоли локализовались в правой половине кишки. Наибольшая частота мутаций KRAS наблюдалась в 12 и 13-м кодонах, составляя 86,7%. У большинства больных встречалась мутация G12V – 25%, за ней следовали G12D – 20% и G12A – 16,6%.
Заключение. Соматические мутации в генах семейства RAS и BRAF при колоректальном раке в Тамбовской области выявлены в 48,4% наблюдений. Среди них отмечается превалирование мутаций KRAS – 81% у лиц женского пола. Онкогенные мутации KRAS являются предикторами ответа на лечение и прогноз.
Ключевые слова: колоректальный рак, соматические мутации, NRAS, KRAS, BRAF
________________________________________________
Aim. To study regional features of tumor genomic landscape in colorectal cancer.
Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage I–IV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females.
Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene – 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%).
Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations – 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.
Keywords: colorectal cancer, somatic mutations, NRAS, KRAS, BRAF
Полный текст
Список литературы
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12. Foltran L, De Maglio G, Pella N, et al. Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. Future Oncol. 2015;11:629-40. DOI:10.2217/fon.14.279
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20. Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42:124-39.
21. Parikh C, Ren R. Mouse model for NRAS-induced leukemogenesis. Methods Enzymol. 2008;439:15-24. DOI:10.1016/S0076-6879(07)00402-8
22. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22. DOI:10.1038/nrc969
23. Vatansever S, Erman B, Gümüş ZH. Oncogenic G12D mutation alters local conformations and dynamics of K-Ras. Scientific Reports. 2019;9(1). DOI:10.1038/s41598-019-48029-z
24. Irahara N, Baba Y, Nosho K, et al. NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology. 2010;19(3):157-63. DOI:10.1097/pdm.0b013e3181c93fd1
25. Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51:1704-13.
26. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2017;141:625-57. DOI:10.5858/arpa.2016-0554-CP
27. Munoz-Maldonado C, Zimmer Y, Medova M. A Comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088. DOI:10.3389/fonc.2019.01088
28. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res. 2004;10(12 Pt 1):4015-21.
DOI:10.1158/1078-0432.CCR-04-0031
29. Qiu YY, Peng D, Wei ZQ, et al. Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis. Can J Gastroenterol Hepatol. 2022;2022:2033876 DOI:10.1155/2022/2033876
30. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272-81. DOI:10.1016/j.ccr.2014.02.017
31. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to geftinib or erlotinib. Plos Med. 2005;2:57-61. DOI:10.1371/journal.pmed.0020017
32. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Ann Oncol. 2006;17:42.
33. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457-67. DOI:10.1158/0008-5472.CAN-11-2612
34. Lu S, Jang H, Muratcioglu S, et al. Ras Conformational Ensembles, Allostery, and Signaling. Chemical Reviews. 2016;116(11):6607-65. DOI:10.1021/acs.chemrev.5b00542
35. Costigan DC, Dong F. The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer. Genes Chromosom. Cancer. 2020;59:152-9.
36. Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116:923-9. DOI:10.1038/bjc.2017.37
37. Demunter A, Stas M, Degreef H, et al. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117:1483-9. DOI:10.1046/j.0022-202x.2001.01601.x
38. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525-32. DOI:10.1056/NEJM198809013190901
39. Nosho K, Kawasaki T, Chan AT, et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588-98.
40. Lan YT, Chang SC, Lin PC, et al. Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer. Cancers. 2021;13(8):1883. DOI:10.3390/cancers13081883
2. Reimers MS, Zeestraten EC, Kuppen PJ, et al. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf). 2013;1:166-83.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67. DOI:10.1016/0092-8674(90)90186-i.
4. Van't Erve I, Wesdorp NJ, Medina JE, et al. KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO precision oncology. 2021;5:PO.21.00223. DOI:10.1200/PO.21.00223
5. Lou E, Xiu J, Baca Y, et al. Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS. Cells. 2021;10(6):1275. DOI:10.3390/cells10061275
6. Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125-36.e3. DOI:10.1016/j.ccell.2017.12.004
7. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205:858-62. DOI:10.1016/j.prp.2009.07.010
8. Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 2014;20:943-56.
9. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol. 2014;53:852-64. DOI:10.3109/0284186X.2014.895036
10. Vale CL, Tierney JF, Fisher D, et al. Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treat Rev. 2012;38:618-25. DOI:10.1016/j.ctrv.2011.11.002
11. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-64.
12. Foltran L, De Maglio G, Pella N, et al. Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. Future Oncol. 2015;11:629-40. DOI:10.2217/fon.14.279
13. Heinemann V, Stintzing S, Kirchner T, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35:262-71.
14. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-6.
15. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619-25.
16. De Rosa M, Pace U, Rega D, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 2015;34:1087-96.
17. Adjei AA. Ras signaling pathway proteins as therapeutic targets. Curr Pharm Des. 2001;7:1581-94.
18. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-9.
19. Tsang AH, Cheng KH, Wong AS, et al. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 2014;20:3847-57.
20. Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42:124-39.
21. Parikh C, Ren R. Mouse model for NRAS-induced leukemogenesis. Methods Enzymol. 2008;439:15-24. DOI:10.1016/S0076-6879(07)00402-8
22. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22. DOI:10.1038/nrc969
23. Vatansever S, Erman B, Gümüş ZH. Oncogenic G12D mutation alters local conformations and dynamics of K-Ras. Scientific Reports. 2019;9(1). DOI:10.1038/s41598-019-48029-z
24. Irahara N, Baba Y, Nosho K, et al. NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology. 2010;19(3):157-63. DOI:10.1097/pdm.0b013e3181c93fd1
25. Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51:1704-13.
26. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2017;141:625-57. DOI:10.5858/arpa.2016-0554-CP
27. Munoz-Maldonado C, Zimmer Y, Medova M. A Comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088. DOI:10.3389/fonc.2019.01088
28. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res. 2004;10(12 Pt 1):4015-21.
DOI:10.1158/1078-0432.CCR-04-0031
29. Qiu YY, Peng D, Wei ZQ, et al. Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis. Can J Gastroenterol Hepatol. 2022;2022:2033876 DOI:10.1155/2022/2033876
30. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272-81. DOI:10.1016/j.ccr.2014.02.017
31. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to geftinib or erlotinib. Plos Med. 2005;2:57-61. DOI:10.1371/journal.pmed.0020017
32. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Ann Oncol. 2006;17:42.
33. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457-67. DOI:10.1158/0008-5472.CAN-11-2612
34. Lu S, Jang H, Muratcioglu S, et al. Ras Conformational Ensembles, Allostery, and Signaling. Chemical Reviews. 2016;116(11):6607-65. DOI:10.1021/acs.chemrev.5b00542
35. Costigan DC, Dong F. The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer. Genes Chromosom. Cancer. 2020;59:152-9.
36. Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116:923-9. DOI:10.1038/bjc.2017.37
37. Demunter A, Stas M, Degreef H, et al. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117:1483-9. DOI:10.1046/j.0022-202x.2001.01601.x
38. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525-32. DOI:10.1056/NEJM198809013190901
39. Nosho K, Kawasaki T, Chan AT, et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588-98.
40. Lan YT, Chang SC, Lin PC, et al. Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer. Cancers. 2021;13(8):1883. DOI:10.3390/cancers13081883
2. Reimers MS, Zeestraten EC, Kuppen PJ, et al. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf). 2013;1:166-83.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67. DOI:10.1016/0092-8674(90)90186-i.
4. Van't Erve I, Wesdorp NJ, Medina JE, et al. KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO precision oncology. 2021;5:PO.21.00223. DOI:10.1200/PO.21.00223
5. Lou E, Xiu J, Baca Y, et al. Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS. Cells. 2021;10(6):1275. DOI:10.3390/cells10061275
6. Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125-36.e3. DOI:10.1016/j.ccell.2017.12.004
7. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205:858-62. DOI:10.1016/j.prp.2009.07.010
8. Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 2014;20:943-56.
9. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol. 2014;53:852-64. DOI:10.3109/0284186X.2014.895036
10. Vale CL, Tierney JF, Fisher D, et al. Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treat Rev. 2012;38:618-25. DOI:10.1016/j.ctrv.2011.11.002
11. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-64.
12. Foltran L, De Maglio G, Pella N, et al. Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. Future Oncol. 2015;11:629-40. DOI:10.2217/fon.14.279
13. Heinemann V, Stintzing S, Kirchner T, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35:262-71.
14. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-6.
15. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619-25.
16. De Rosa M, Pace U, Rega D, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 2015;34:1087-96.
17. Adjei AA. Ras signaling pathway proteins as therapeutic targets. Curr Pharm Des. 2001;7:1581-94.
18. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-9.
19. Tsang AH, Cheng KH, Wong AS, et al. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 2014;20:3847-57.
20. Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42:124-39.
21. Parikh C, Ren R. Mouse model for NRAS-induced leukemogenesis. Methods Enzymol. 2008;439:15-24. DOI:10.1016/S0076-6879(07)00402-8
22. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22. DOI:10.1038/nrc969
23. Vatansever S, Erman B, Gümüş ZH. Oncogenic G12D mutation alters local conformations and dynamics of K-Ras. Scientific Reports. 2019;9(1). DOI:10.1038/s41598-019-48029-z
24. Irahara N, Baba Y, Nosho K, et al. NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology. 2010;19(3):157-63. DOI:10.1097/pdm.0b013e3181c93fd1
25. Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51:1704-13.
26. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2017;141:625-57. DOI:10.5858/arpa.2016-0554-CP
27. Munoz-Maldonado C, Zimmer Y, Medova M. A Comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088. DOI:10.3389/fonc.2019.01088
28. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res. 2004;10(12 Pt 1):4015-21.
DOI:10.1158/1078-0432.CCR-04-0031
29. Qiu YY, Peng D, Wei ZQ, et al. Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis. Can J Gastroenterol Hepatol. 2022;2022:2033876 DOI:10.1155/2022/2033876
30. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272-81. DOI:10.1016/j.ccr.2014.02.017
31. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to geftinib or erlotinib. Plos Med. 2005;2:57-61. DOI:10.1371/journal.pmed.0020017
32. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Ann Oncol. 2006;17:42.
33. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457-67. DOI:10.1158/0008-5472.CAN-11-2612
34. Lu S, Jang H, Muratcioglu S, et al. Ras Conformational Ensembles, Allostery, and Signaling. Chemical Reviews. 2016;116(11):6607-65. DOI:10.1021/acs.chemrev.5b00542
35. Costigan DC, Dong F. The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer. Genes Chromosom. Cancer. 2020;59:152-9.
36. Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116:923-9. DOI:10.1038/bjc.2017.37
37. Demunter A, Stas M, Degreef H, et al. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117:1483-9. DOI:10.1046/j.0022-202x.2001.01601.x
38. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525-32. DOI:10.1056/NEJM198809013190901
39. Nosho K, Kawasaki T, Chan AT, et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588-98.
40. Lan YT, Chang SC, Lin PC, et al. Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer. Cancers. 2021;13(8):1883. DOI:10.3390/cancers13081883
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2. Reimers MS, Zeestraten EC, Kuppen PJ, et al. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf). 2013;1:166-83.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67. DOI:10.1016/0092-8674(90)90186-i.
4. Van't Erve I, Wesdorp NJ, Medina JE, et al. KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO precision oncology. 2021;5:PO.21.00223. DOI:10.1200/PO.21.00223
5. Lou E, Xiu J, Baca Y, et al. Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS. Cells. 2021;10(6):1275. DOI:10.3390/cells10061275
6. Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125-36.e3. DOI:10.1016/j.ccell.2017.12.004
7. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205:858-62. DOI:10.1016/j.prp.2009.07.010
8. Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 2014;20:943-56.
9. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol. 2014;53:852-64. DOI:10.3109/0284186X.2014.895036
10. Vale CL, Tierney JF, Fisher D, et al. Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treat Rev. 2012;38:618-25. DOI:10.1016/j.ctrv.2011.11.002
11. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-64.
12. Foltran L, De Maglio G, Pella N, et al. Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. Future Oncol. 2015;11:629-40. DOI:10.2217/fon.14.279
13. Heinemann V, Stintzing S, Kirchner T, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35:262-71.
14. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-6.
15. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619-25.
16. De Rosa M, Pace U, Rega D, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 2015;34:1087-96.
17. Adjei AA. Ras signaling pathway proteins as therapeutic targets. Curr Pharm Des. 2001;7:1581-94.
18. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-9.
19. Tsang AH, Cheng KH, Wong AS, et al. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 2014;20:3847-57.
20. Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42:124-39.
21. Parikh C, Ren R. Mouse model for NRAS-induced leukemogenesis. Methods Enzymol. 2008;439:15-24. DOI:10.1016/S0076-6879(07)00402-8
22. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22. DOI:10.1038/nrc969
23. Vatansever S, Erman B, Gümüş ZH. Oncogenic G12D mutation alters local conformations and dynamics of K-Ras. Scientific Reports. 2019;9(1). DOI:10.1038/s41598-019-48029-z
24. Irahara N, Baba Y, Nosho K, et al. NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology. 2010;19(3):157-63. DOI:10.1097/pdm.0b013e3181c93fd1
25. Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51:1704-13.
26. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2017;141:625-57. DOI:10.5858/arpa.2016-0554-CP
27. Munoz-Maldonado C, Zimmer Y, Medova M. A Comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088. DOI:10.3389/fonc.2019.01088
28. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res. 2004;10(12 Pt 1):4015-21.
DOI:10.1158/1078-0432.CCR-04-0031
29. Qiu YY, Peng D, Wei ZQ, et al. Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis. Can J Gastroenterol Hepatol. 2022;2022:2033876 DOI:10.1155/2022/2033876
30. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272-81. DOI:10.1016/j.ccr.2014.02.017
31. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to geftinib or erlotinib. Plos Med. 2005;2:57-61. DOI:10.1371/journal.pmed.0020017
32. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Ann Oncol. 2006;17:42.
33. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457-67. DOI:10.1158/0008-5472.CAN-11-2612
34. Lu S, Jang H, Muratcioglu S, et al. Ras Conformational Ensembles, Allostery, and Signaling. Chemical Reviews. 2016;116(11):6607-65. DOI:10.1021/acs.chemrev.5b00542
35. Costigan DC, Dong F. The extended spectrum of RAS-MAPK pathway mutations in colorectal cancer. Genes Chromosom. Cancer. 2020;59:152-9.
36. Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116:923-9. DOI:10.1038/bjc.2017.37
37. Demunter A, Stas M, Degreef H, et al. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117:1483-9. DOI:10.1046/j.0022-202x.2001.01601.x
38. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525-32. DOI:10.1056/NEJM198809013190901
39. Nosho K, Kawasaki T, Chan AT, et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588-98.
40. Lan YT, Chang SC, Lin PC, et al. Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer. Cancers. 2021;13(8):1883. DOI:10.3390/cancers13081883
Авторы
Н.А. Огнерубов*1,2, Е.Н. Ежова2
1 ФГБОУ ВО «Тамбовский государственный университет им. Г.Р. Державина», Тамбов, Россия;
2 ГБУЗ «Тамбовский областной онкологический клинический диспансер», Тамбов, Россия
*ognerubov_n.a@mail.ru
1 Derzhavin Tambov State University, Tambov, Russia;
2 Tambov Regional Oncological Clinical Dispensary, Tambov, Russia
*ognerubov_n.a@mail.ru
1 ФГБОУ ВО «Тамбовский государственный университет им. Г.Р. Державина», Тамбов, Россия;
2 ГБУЗ «Тамбовский областной онкологический клинический диспансер», Тамбов, Россия
*ognerubov_n.a@mail.ru
________________________________________________
1 Derzhavin Tambov State University, Tambov, Russia;
2 Tambov Regional Oncological Clinical Dispensary, Tambov, Russia
*ognerubov_n.a@mail.ru
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