Different clinicopathological characteristics in Indonesian colorectal patients with RAS mutations and LC3 over-expression: a cross-sectional study

Rio Andreas; Reno Rudiman; Kiki Lukman; Bambang Am Am Setya Sulthana; Andriana Purnama; Mochammad Riskie Aditya Putra; Prapanca Nugraha; Etis Primastari

doi:10.15562/bmj.v12i2.4519

Different clinicopathological characteristics in Indonesian colorectal patients with RAS mutations and LC3 over-expression: a cross-sectional study

Rio Andreas ,

Reno Rudiman ,

Kiki Lukman ,

Bambang Am Am Setya Sulthana ,

Andriana Purnama ,

Mochammad Riskie Aditya Putra ,

Prapanca Nugraha ,

Etis Primastari ,

pdf |
DOI: https://doi.org/10.15562/bmj.v12i2.4519 |
Published: 2023-06-03

Abstract

Link of Video Abstract: https://youtu.be/9Gip7ztxLJk

Background: Colorectal cancer is reaching the third highest incidence globally, including in Indonesia. Members of the RAS family are frequently discovered in colorectal cancers and may be a contributing factor for the successfulness of anti-epidermal growth factor receptor monoclonal antibodies therapy. Microtubule-associated protein 1 light chain 3 (LC3) is one of the autophagy markers in colorectal cancer cells routinely tested. The relevance of RAS mutation and expression of LC3 as a prognostic factor in CRC has so far only been discussed in several reports. This study aimed to describe the different clinicopathological characteristics of colorectal patients with mutations of the RAS family and LC3 overexpression.

Methods: This study was a cross-sectional study, and the subjects for this study were patient from the Digestive Surgery division at the Tertiary Hospital in West Java, Indonesia with colorectal cancer. A total of 40 study subjects were included in this study. Examination of RAS mutations was carried out by polymerase chain reaction. Meanwhile, the LC3 examination was performed with immunohistochemistry.

Results: The RAS family mutation, which is a mutation of either KRAS, NRAS, or both, was shown in 22 (55%) colorectal cancer patients, and a positive LC3 test was shown in 24 (60%) patients. A univariate analysis of the mutations of the RAS family and expression of the LC3 showed non-significant relationships.

Conclusion: No association observed between RAS family mutations and LC3 expression in colorectal cancer patients.

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249.
Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 2018;37(1):1–10.
Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059-2072.
Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Molecular cancer. 2021;20(1):1-7.
Afrăsânie VA, Marinca MV, Alexa-Stratulat T, Gafton B, Păduraru M, Adavidoaiei AM, et al. KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer–practical implications for the clinician. Radiology and oncology. 2019;53(3):265.
Zanatto RM, Santos G, Oliveira JC, Pracucho EM, Nunes AJ, Lopes-Filho GJ, et al. Impact of KRAS mutations in clinical feature in colorectal cancer. Arq Bras Cir Dig. 2020:16;33(3):e1524.
Bronte G, Silvestris N, Castiglia M, Galvano A, Passiglia F, Sortino G, et al. New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?. Oncotarget. 2015;6(28):24780.
Wu S, Sun C, Tian D, Li Y, Gao X, He S, Li T. Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. International journal of clinical and experimental pathology. 2015;8(4):3882.
Burada F, Nicoli ER, Ciurea ME, Uscatu DC, Ioana M, Gheonea DI. Autophagy in colorectal cancer: An important switch from physiology to pathology. World journal of gastrointestinal oncology. 2015;7(11):271.
Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330(6009):1344-8.
Cuschieri S. The STROBE guidelines. Saudi journal of anaesthesia. 2019;13(Suppl 1):S31.
László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, et al. Recent updates on the significance of KRAS mutations in colorectal cancer biology. Cells. 2021;10(3):667.
Rudiman R, Wijaya A, Sribudiani Y, Soedjana HS, Wiraswati HL, Primastari, et al. Identification of KRAS mutation and HER2 expression in Indonesian colorectal cancer population: a cross-sectional study. Annals of Medicine & Surgery. 2023;85(5):1761-1768.
Lukman K, Reza AT, Hasibuan LY, Sribudiani Y, Dewayani BM, Rudiman R, et al. Different clinicopathological characteristics in indonesian colorectal patients with NRAS mutations and HER2 over-expression. Asian Pac J Cancer Prev. 2023;24(4):1373–1377.
Levi M, Prayogi G, Sastranagara F, Sudianto E, Widjajahakim G, Gani W, et al. Clinicopathological associations of K-RAS and N-RAS mutations in Indonesian colorectal cancer cohort. Journal of gastrointestinal cancer. 2018;49:124-131.
Alghamdi M, Alabdullatif N, Al-Rashoud A, Alotaibi J, Alhussaini N, Elsirawani S, et al. KRAS mutations in colorectal cancer: relationship with clinicopathological characteristics and impact on clinical outcomes in Saudi Arabia. Cureus. 2022;14(3): e23656.
Sanchez-Ibarra HE, Jiang X, Gallegos-Gonzalez EY, Cavazos-González AC, Chen Y, Morcos F, et al. KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study. PloS one. 2020;15(7):e0235490.
Giatromanolaki A, Koukourakis MI, Harris AL, Polychronidis A, Gatter KC, Sivridis E. Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas. Journal of clinical pathology. 2010;63(10):867-872.
Wang Y, Zhao Z, Zhuang J, Wu X, Wang Z, Zhang B, et al. Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer. J Cancer. 2021 2;12(12):3515.
Zheng HY, Zhang XY, Wang XF, Sun BC. Autophagy enhances the aggressiveness of human colorectal cancer cells and their ability to adapt to apoptotic stimulus. Cancer biology & medicine. 2012;9(2):105.
Schmitz KJ, Ademi C, Bertram S, Schmid KW, Baba HA. Prognostic relevance of autophagy-related markers LC3, p62/sequestosome 1, Beclin-1 and ULK1 in colorectal cancer patients with respect to KRAS mutational status. World journal of surgical oncology. 2016;14(1):1-3.
Zhao H, Yang M, Zhao B. Beclin 1 and LC3 as predictive biomarkers for metastatic colorectal carcinoma. Oncotarget. 2017;8(35):59058.
Guo GF, Jiang WQ, Zhang B, Cai YC, Xu RH, Chen XX, et al. Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer. World J Gastroenterol. 2011;17(43):4779–86.
Prajitno JH, Pranoto A, Adiwinoto RD, Soelistijo SA. The effect of metformin on autophagy by LC3 expression in type 2 diabetes mellitus (T2DM) human skeletal muscle cell culture. Bali Med J. 2022;11(1):349-355.
Sideras K, Galjart B, Vasaturo A, Pedroza-Gonzalez A, Biermann K, Mancham S, et al. Prognostic value of intra‐tumoral CD8+/FoxP3+ lymphocyte ratio in patients with resected colorectal cancer liver metastasis. J Surg Oncol. 2018;118(1):68.
Guo GF, Wang YX, Zhang YJ, Chen XX, Lu JB, Wang HH, et al. Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data. World journal of gastroenterology. 2019;25(15):1840.

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249.

[2] Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 2018;37(1):1–10.

[3] Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059-2072.

[4] Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Molecular cancer. 2021;20(1):1-7.

[5] Afrăsânie VA, Marinca MV, Alexa-Stratulat T, Gafton B, Păduraru M, Adavidoaiei AM, et al. KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer–practical implications for the clinician. Radiology and oncology. 2019;53(3):265.

[6] Zanatto RM, Santos G, Oliveira JC, Pracucho EM, Nunes AJ, Lopes-Filho GJ, et al. Impact of KRAS mutations in clinical feature in colorectal cancer. Arq Bras Cir Dig. 2020:16;33(3):e1524.

[7] Bronte G, Silvestris N, Castiglia M, Galvano A, Passiglia F, Sortino G, et al. New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?. Oncotarget. 2015;6(28):24780.

[8] Wu S, Sun C, Tian D, Li Y, Gao X, He S, Li T. Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. International journal of clinical and experimental pathology. 2015;8(4):3882.

[9] Burada F, Nicoli ER, Ciurea ME, Uscatu DC, Ioana M, Gheonea DI. Autophagy in colorectal cancer: An important switch from physiology to pathology. World journal of gastrointestinal oncology. 2015;7(11):271.

[10] Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330(6009):1344-8.

[11] Cuschieri S. The STROBE guidelines. Saudi journal of anaesthesia. 2019;13(Suppl 1):S31.

[12] László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, et al. Recent updates on the significance of KRAS mutations in colorectal cancer biology. Cells. 2021;10(3):667.

[13] Rudiman R, Wijaya A, Sribudiani Y, Soedjana HS, Wiraswati HL, Primastari, et al. Identification of KRAS mutation and HER2 expression in Indonesian colorectal cancer population: a cross-sectional study. Annals of Medicine & Surgery. 2023;85(5):1761-1768.

[14] Lukman K, Reza AT, Hasibuan LY, Sribudiani Y, Dewayani BM, Rudiman R, et al. Different clinicopathological characteristics in indonesian colorectal patients with NRAS mutations and HER2 over-expression. Asian Pac J Cancer Prev. 2023;24(4):1373–1377.

[15] Levi M, Prayogi G, Sastranagara F, Sudianto E, Widjajahakim G, Gani W, et al. Clinicopathological associations of K-RAS and N-RAS mutations in Indonesian colorectal cancer cohort. Journal of gastrointestinal cancer. 2018;49:124-131.

[16] Alghamdi M, Alabdullatif N, Al-Rashoud A, Alotaibi J, Alhussaini N, Elsirawani S, et al. KRAS mutations in colorectal cancer: relationship with clinicopathological characteristics and impact on clinical outcomes in Saudi Arabia. Cureus. 2022;14(3): e23656.

[17] Sanchez-Ibarra HE, Jiang X, Gallegos-Gonzalez EY, Cavazos-González AC, Chen Y, Morcos F, et al. KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study. PloS one. 2020;15(7):e0235490.

[18] Giatromanolaki A, Koukourakis MI, Harris AL, Polychronidis A, Gatter KC, Sivridis E. Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas. Journal of clinical pathology. 2010;63(10):867-872.

[19] Wang Y, Zhao Z, Zhuang J, Wu X, Wang Z, Zhang B, et al. Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer. J Cancer. 2021 2;12(12):3515.

[20] Zheng HY, Zhang XY, Wang XF, Sun BC. Autophagy enhances the aggressiveness of human colorectal cancer cells and their ability to adapt to apoptotic stimulus. Cancer biology & medicine. 2012;9(2):105.

[21] Schmitz KJ, Ademi C, Bertram S, Schmid KW, Baba HA. Prognostic relevance of autophagy-related markers LC3, p62/sequestosome 1, Beclin-1 and ULK1 in colorectal cancer patients with respect to KRAS mutational status. World journal of surgical oncology. 2016;14(1):1-3.

[22] Zhao H, Yang M, Zhao B. Beclin 1 and LC3 as predictive biomarkers for metastatic colorectal carcinoma. Oncotarget. 2017;8(35):59058.

[23] Guo GF, Jiang WQ, Zhang B, Cai YC, Xu RH, Chen XX, et al. Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer. World J Gastroenterol. 2011;17(43):4779–86.

[24] Prajitno JH, Pranoto A, Adiwinoto RD, Soelistijo SA. The effect of metformin on autophagy by LC3 expression in type 2 diabetes mellitus (T2DM) human skeletal muscle cell culture. Bali Med J. 2022;11(1):349-355.

[25] Sideras K, Galjart B, Vasaturo A, Pedroza-Gonzalez A, Biermann K, Mancham S, et al. Prognostic value of intra‐tumoral CD8+/FoxP3+ lymphocyte ratio in patients with resected colorectal cancer liver metastasis. J Surg Oncol. 2018;118(1):68.

[26] Guo GF, Wang YX, Zhang YJ, Chen XX, Lu JB, Wang HH, et al. Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data. World journal of gastroenterology. 2019;25(15):1840.

Different clinicopathological characteristics in Indonesian colorectal patients with RAS mutations and LC3 over-expression: a cross-sectional study

Abstract

References

How to Cite

Search Panel