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Clinicopathological Evaluation of KRAS Mutations and Their Relationship with P21 Immunohistochemical Expression in Colorectal Carcinoma

Year 2025, Volume: 6 Issue: 3, 269 - 278
https://doi.org/10.46871/eams.1757628

Abstract

Purpose: This study aims to evaluate the clinicopathological significance of KRAS mutations and the immunohistochemical expression of p21 in colorectal carcinoma (CRC), and to explore their correlation with various pathological parameters.
Materials and Methods: A total of 30 metastatic CRC cases diagnosed and/or treated at Ankara Oncology Training and Research Hospital were retrospectively analyzed. KRAS mutation analysis was conducted using pyrosequencing, and p21 expression was evaluated via immunohistochemistry. Associations between KRAS mutation status, p21 expression, and clinicopathological variables including tumor grade, size, invasion depth, and lymph node status were statistically analyzed.
Results: KRAS mutations were identified in 15 (50%) of the cases, with codon 12 mutations being the most frequent. p21 nuclear expression was observed more commonly in KRAS mutant tumors. A significant association was found between p21 expression and pathological tumor invasion depth. No significant correlation was detected between KRAS mutations and tumor localization, grade, or other parameters.
Conclusion: KRAS mutations, particularly at codon 12, are common in CRC and may influence p21 expression. The findings suggest a potential link between KRAS mutation and the molecular regulation of p21, warranting further investigation in larger cohorts.

References

  • 1. Boyle P, Levin B, editors. World Cancer Report 2008. Lyon (France): IARC; 2008.
  • 2. Ferlay J, Bray F, Pisani P, Parkin M. Cancer incidence, mortality and prevalence worldwide. Globocan 2002. Lyon: IARC CancerBase No. 5; 2004.
  • 3. Büyükdoğan M. Kolorektal kanserde genetik ve etiyolojik faktörler. Selcuk Tip Derg. 2009;25(3):171–80.
  • 4. Stang A, Kluttig A. Etiologic insights from surface adjustment of colorectal carcinoma incidences: an analysis of the U.S. SEER data 2000–2004. Am J Gastroenterol. 2008;103:2853–61.
  • 5. Mendeloff AI. Dietary fiber and the gastrointestinal tract. In: Beek JE, editor. Developments in Digestive Diseases. Philadelphia: Lea & Febiger; 1979.
  • 6. Weisburger JH. Causes, relevant mechanisms, and prevention of large bowel cancer. Semin Oncol. 1991;18:316–36.
  • 7. Forte A, De SR, Leonetti G, Manfredelli S, Urbano V, Bezzi M. Dietary chemoprevention.
  • 8. Marshall JR. Prevention of colorectal cancer: diet, chemoprevention, and lifestyle. Gastroenterol Clin North Am. 2008;37:73–82.
  • 9. Van Duijnhoven FJ, Bueno-de-Mesquita HB, Ferrari P, Jenab M, Boshuizen HC, Ros MM, et al. Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2009;89:1441–52.
  • 10. Andreyev HJ, Norman AR, Cunningham D, Oates J, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst. 1998;90(9):675–84.
  • 11. Seeburg PH, Colby WW, Capon DJ, Goeddel DV, Levinson AD. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984;312:71–5.
  • 12. Bukholm IK, Nesland JM. Protein expression of p53, p21(WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas. Virchows Arch. 2000;436:224–8.
  • 13. Zirbes TK, Baldus SE, Moenig SP, Nolden S, Kunze D, Shafizadeh ST, et al. Prognostic impact of p21/WAF1/CIP1 in colorectal cancer. Int J Cancer. 2000;89:14–8.
  • 14. Lee J, Jang KT, Ki CS, et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007;109:1561–9.
  • 15. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993;73:611–20.
  • 16. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.
  • 17. Watanabe T, Yoshino T, Uetake H, et al. KRAS mutational status in Japanese patients with colorectal cancer: results from a nationwide, multicenter, cross-sectional study. Jpn J Clin Oncol. 2013;43(7):706–12.
  • 18. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer. J Clin Oncol. 2010;28:466–74.
  • 19. Abubaker J, Bavi P, Al-Haqawi W, et al. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol. 2009;219:435–45.
  • 20. Barault L, Veyrie N, Jooste V, et al. Mutations in the RAS-MAPK, PI(3)K signaling network correlate with poor survival in colon cancers. Int J Cancer. 2008;122:2255–9.
  • 21. Samowitz WS, Curtin K, Schaffer D, et al. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival. Cancer Epidemiol Biomarkers Prev. 2000;9:1193–7.
  • 22. 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.
  • 23. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in colorectal cancer: the "RASCAL II" study. Br J Cancer. 2001;85:692–6.
  • 24. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.
  • 25. Moerkerk P, Arends JW, van Driel M, et al. Type and number of Ki-ras point mutations relate to stage of human colorectal cancer. Cancer Res. 1994;54:3376–8.
  • 26. Span M, Moerkerk PT, De Goeij AF, Arends JW. K-ras point mutations in relation to tumor progression and survival in colorectal cancer. Int J Cancer. 1996;69:241–5.
  • 27. Urosevic N, Krtolica K, Skaro-Milic A, et al. Prevalence of G-to-T transversions among K-ras mutations in human colorectal tumors. Int J Cancer. 1993;54:249–54.
  • 28. Ferreira CG, Zalcberg-Renault I, Vieira FM, et al. Analysis of KRAS mutations in colorectal cancer patients by gender in a Brazilian cohort. J Clin Oncol. 2010;28(15 Suppl):3614.
  • 29. Nash GM, Gimbel M, Shia J, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 2010;17:572–8.
  • 30. Santini D, Loupakis F, Vincenzi B, et al. High concordance of KRAS status between primary colorectal tumors and metastatic sites. Oncologist. 2008;13:1270–5.
  • 31. Gao J, Zhang J, Lu T, et al. Correlation between KRAS mutations and clinicopathologic features in colorectal carcinomas. Zhonghua Bing Li Xue Za Zhi. 2012;41(9):595–8.
  • 32. Sharpe CC, Dockrell ME, Scott R, et al. Evidence of a role for Ki-Ras in the stimulated proliferation of renal fibroblasts. J Am Soc Nephrol. 1999;10:1186–1192.
  • 33. Anttila MA, Kosma VM, Hongxiu J, et al. p21/WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations. Br J Cancer. 1999;79:1870–8.
  • 34. Gartel AL, Radhakrishnan SK. p21(WAF1/CIP1): a critical mediator of cellular responses to external and internal stress. Cancer Res. 2005;65:3980–5.
  • 35. Ioachim E. Expression of cyclins and cyclin-dependent kinase inhibitors in colorectal carcinoma. Int J Clin Pract. 2008;62(11):1736–43.
  • 36. Asmis TR, Powell E, Karapetis CS, Jonker DJ. Comorbidity, age and overall survival in cetuximabtreated patients with advanced colorectal cancer (ACRC)--results from 110 NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care, Ann Oncol. 2010 jul 5.
  • 37. Tol I, Dijkstra JR, Klomp M, Teerenstra S. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab, Eur J Cancer. 2010 Jul;46(11):1997-2009.

Kolorektal Karsinomlarda KRAS Mutasyon Varlığının ve p21 İmmünohistokimyasal Ekspresyonunun Klinikopatolojik Parametrelerle İlişkisi

Year 2025, Volume: 6 Issue: 3, 269 - 278
https://doi.org/10.46871/eams.1757628

Abstract

Amaç: Bu çalışmada, kolorektal karsinom (KRK) olgularında KRAS mutasyonlarının klinikopatolojik önemi ile p21 immünohistokimyasal ekspresyonu değerlendirilmiş ve bu biyobelirteçlerin çeşitli patolojik parametrelerle ilişkisi araştırılmıştır.
Gereç ve Yöntem: Ankara Onkoloji Eğitim ve Araştırma Hastanesi’nde tanı almış ve/veya tedavi edilmiş 30 metastatik KRK olgusu retrospektif olarak incelenmiştir. KRAS mutasyon analizi pirodizi yöntemiyle, p21 ekspresyonu ise immünohistokimyasal olarak değerlendirilmiştir. KRAS mutasyon durumu, p21 ekspresyonu ve klinikopatolojik değişkenler (tümör derecesi, boyutu, invazyon derinliği, lenf nodu durumu vb.) arasındaki ilişkiler istatistiksel olarak analiz edilmiştir.
Bulgular: Olguların %50’sinde KRAS mutasyonu saptanmış olup, en sık mutasyon kodon 12’de gözlenmiştir. KRAS mutasyonlu olgularda p21 nükleer ekspresyonu daha yaygındı. p21 ekspresyonu ile patolojik tümör invazyon derinliği arasında anlamlı ilişki bulunmuştur. KRAS mutasyonu ile tümör lokalizasyonu, derecesi veya diğer parametreler arasında anlamlı bir ilişki saptanmamıştır.
Sonuç: KRAS mutasyonları, özellikle kodon 12 düzeyindeki değişiklikler, KRK olgularında yaygın olarak gözlenmektedir ve p21 ekspresyonunu etkileyebilmektedir. Bulgular, KRAS mutasyonu ile p21’in moleküler düzenlenmesi arasında olası bir ilişki olduğunu düşündürmekte olup, daha geniş örneklem gruplarında yapılacak ileri çalışmalarla desteklenmelidir.

Ethical Statement

ETİK KURUL ONAY BELGESİ Bu çalışma için Dr. Abdurrahman Yurtaslan Ankara Onkoloji Eğitim ve Araştırma Hastanesi Klinik Araştırmalar Etik Kurulu’ndan 22.03.2012 tarihinde, 2012/108 sayılı karar ile etik kurul onayı alınmıştır. Karar No: 2012/108 Karar Tarihi: 22.03.2012 Etik Kurul: Dr. Abdurrahman Yurtaslan Ankara Onkoloji EAH Klinik Araştırmalar Etik Kurulu Araştırmacı: Dr. Burçin Çelik Çalışma Başlığı: Kolorektal Karsinomlarda K-RAS Mutasyon Varlığının ve P21 İmmünohistokimyasal Ekspresyonunun Klinikopatolojik Parametrelerle İlişkisi

References

  • 1. Boyle P, Levin B, editors. World Cancer Report 2008. Lyon (France): IARC; 2008.
  • 2. Ferlay J, Bray F, Pisani P, Parkin M. Cancer incidence, mortality and prevalence worldwide. Globocan 2002. Lyon: IARC CancerBase No. 5; 2004.
  • 3. Büyükdoğan M. Kolorektal kanserde genetik ve etiyolojik faktörler. Selcuk Tip Derg. 2009;25(3):171–80.
  • 4. Stang A, Kluttig A. Etiologic insights from surface adjustment of colorectal carcinoma incidences: an analysis of the U.S. SEER data 2000–2004. Am J Gastroenterol. 2008;103:2853–61.
  • 5. Mendeloff AI. Dietary fiber and the gastrointestinal tract. In: Beek JE, editor. Developments in Digestive Diseases. Philadelphia: Lea & Febiger; 1979.
  • 6. Weisburger JH. Causes, relevant mechanisms, and prevention of large bowel cancer. Semin Oncol. 1991;18:316–36.
  • 7. Forte A, De SR, Leonetti G, Manfredelli S, Urbano V, Bezzi M. Dietary chemoprevention.
  • 8. Marshall JR. Prevention of colorectal cancer: diet, chemoprevention, and lifestyle. Gastroenterol Clin North Am. 2008;37:73–82.
  • 9. Van Duijnhoven FJ, Bueno-de-Mesquita HB, Ferrari P, Jenab M, Boshuizen HC, Ros MM, et al. Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2009;89:1441–52.
  • 10. Andreyev HJ, Norman AR, Cunningham D, Oates J, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst. 1998;90(9):675–84.
  • 11. Seeburg PH, Colby WW, Capon DJ, Goeddel DV, Levinson AD. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984;312:71–5.
  • 12. Bukholm IK, Nesland JM. Protein expression of p53, p21(WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas. Virchows Arch. 2000;436:224–8.
  • 13. Zirbes TK, Baldus SE, Moenig SP, Nolden S, Kunze D, Shafizadeh ST, et al. Prognostic impact of p21/WAF1/CIP1 in colorectal cancer. Int J Cancer. 2000;89:14–8.
  • 14. Lee J, Jang KT, Ki CS, et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007;109:1561–9.
  • 15. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993;73:611–20.
  • 16. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.
  • 17. Watanabe T, Yoshino T, Uetake H, et al. KRAS mutational status in Japanese patients with colorectal cancer: results from a nationwide, multicenter, cross-sectional study. Jpn J Clin Oncol. 2013;43(7):706–12.
  • 18. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer. J Clin Oncol. 2010;28:466–74.
  • 19. Abubaker J, Bavi P, Al-Haqawi W, et al. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol. 2009;219:435–45.
  • 20. Barault L, Veyrie N, Jooste V, et al. Mutations in the RAS-MAPK, PI(3)K signaling network correlate with poor survival in colon cancers. Int J Cancer. 2008;122:2255–9.
  • 21. Samowitz WS, Curtin K, Schaffer D, et al. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival. Cancer Epidemiol Biomarkers Prev. 2000;9:1193–7.
  • 22. 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.
  • 23. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in colorectal cancer: the "RASCAL II" study. Br J Cancer. 2001;85:692–6.
  • 24. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.
  • 25. Moerkerk P, Arends JW, van Driel M, et al. Type and number of Ki-ras point mutations relate to stage of human colorectal cancer. Cancer Res. 1994;54:3376–8.
  • 26. Span M, Moerkerk PT, De Goeij AF, Arends JW. K-ras point mutations in relation to tumor progression and survival in colorectal cancer. Int J Cancer. 1996;69:241–5.
  • 27. Urosevic N, Krtolica K, Skaro-Milic A, et al. Prevalence of G-to-T transversions among K-ras mutations in human colorectal tumors. Int J Cancer. 1993;54:249–54.
  • 28. Ferreira CG, Zalcberg-Renault I, Vieira FM, et al. Analysis of KRAS mutations in colorectal cancer patients by gender in a Brazilian cohort. J Clin Oncol. 2010;28(15 Suppl):3614.
  • 29. Nash GM, Gimbel M, Shia J, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 2010;17:572–8.
  • 30. Santini D, Loupakis F, Vincenzi B, et al. High concordance of KRAS status between primary colorectal tumors and metastatic sites. Oncologist. 2008;13:1270–5.
  • 31. Gao J, Zhang J, Lu T, et al. Correlation between KRAS mutations and clinicopathologic features in colorectal carcinomas. Zhonghua Bing Li Xue Za Zhi. 2012;41(9):595–8.
  • 32. Sharpe CC, Dockrell ME, Scott R, et al. Evidence of a role for Ki-Ras in the stimulated proliferation of renal fibroblasts. J Am Soc Nephrol. 1999;10:1186–1192.
  • 33. Anttila MA, Kosma VM, Hongxiu J, et al. p21/WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations. Br J Cancer. 1999;79:1870–8.
  • 34. Gartel AL, Radhakrishnan SK. p21(WAF1/CIP1): a critical mediator of cellular responses to external and internal stress. Cancer Res. 2005;65:3980–5.
  • 35. Ioachim E. Expression of cyclins and cyclin-dependent kinase inhibitors in colorectal carcinoma. Int J Clin Pract. 2008;62(11):1736–43.
  • 36. Asmis TR, Powell E, Karapetis CS, Jonker DJ. Comorbidity, age and overall survival in cetuximabtreated patients with advanced colorectal cancer (ACRC)--results from 110 NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care, Ann Oncol. 2010 jul 5.
  • 37. Tol I, Dijkstra JR, Klomp M, Teerenstra S. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab, Eur J Cancer. 2010 Jul;46(11):1997-2009.
There are 37 citations in total.

Details

Primary Language English
Subjects Pathology, Cancer Genetics, Predictive and Prognostic Markers
Journal Section Research Articles
Authors

Burçin Çelik 0000-0001-5879-477X

Olcay Kandemir 0000-0002-5293-7837

Early Pub Date November 7, 2025
Publication Date November 15, 2025
Submission Date August 4, 2025
Acceptance Date October 10, 2025
Published in Issue Year 2025 Volume: 6 Issue: 3

Cite

Vancouver Çelik B, Kandemir O. Clinicopathological Evaluation of KRAS Mutations and Their Relationship with P21 Immunohistochemical Expression in Colorectal Carcinoma. Exp Appl Med Sci. 2025;6(3):269-78.

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