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Correlation between KRAS and NRAS mutational status and clinicopathological features in 414 cases of metastatic colorectal cancer in Morocco: the largest North African case series

Abstract

Background

Advances in molecular biology have improved understanding of the molecular features of carcinogenesis and progression of colorectal cancer. It is clear that the efficacy of anti-EGFR depends upon the RAS mutational status, since any mutation in RAS is associated with resistance to anti-EGFR therapy. The aim of this study is to report the largest North African description of KRAS and NRAS status in metastatic colorectal cancer and to describe the association of these mutations with clinicopathological characteristics.

Methods

This is a prospective study of all consecutive unselected metastatic colorectal cancer samples, collected from the Laboratory of Pathology at the National Institute of Oncology of Rabat, Morocco, from January 1st 2020 to December 31st 2021. The molecular analysis was performed on the Idylla™ platform (fully automated real-time polymerase chain reaction-based assay) for KRAS and NRAS mutations in exons 2, 3 and 4. These mutations were correlated to gender, primary tumor site, histological type and degree of differentiation of tumor using adequate statistical methods.

Results

Four hundred fourteen colorectal tumors were screened for KRAS and NRAS mutations. These mutations occurred in 51.7% of tumors for KRAS (mainly in exon 12) and in 3% of tumors for NRAS. There was a significant correlation between NRAS mutation and age of colorectal patients in this study. The low rate of invalid RAS tests (1.7% for KRAS and 3.1% for NRAS) was certainly obtained due to the strict respect of pre-analytical factors such as cold ischemia time and formalin fixation.

Conclusion

We report the largest North African analysis of NRAS and KRAS status in colorectal metastatic patients. This study showed the ability in low middle income countries to perform a high rate of valid tests and the unusual trend towards older patients for NRAS mutations.

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Background

Colorectal cancer (CRC) is the second most common cause of cancer deaths [1]. Approximately 20% of patients with CRC present with metastases at the time of diagnosis [1]. Metastatic and recurrent diseases are associated with poor survival [2]. Advances in molecular biology have improved understanding of the molecular features of carcinogenesis and progression of CRC. Thus, the identification of prognostic and predictive biomarkers made it possible to refine prognosis in order to prescribe targeted therapies as part of a personalized medicine. In this context, it has been demonstrated that Epidermal growth factor receptor (EGFR) signaling is an important intracellular signaling pathway in CRC development and progression. RAS (for rat sarcoma virus) proteins are downstream signaling molecules of EGFR [3, 4]. There are three isoforms of RAS: KRAS, NRAS and HRAS [3, 4]. The efficacy of anti-EGFR depends upon the RAS mutational status. Mutations in RAS are associated with resistance to anti-EGFR therapy [3, 5,6,7,8]. HRAS is rarely mutated in CRC [3]. Treatment guidelines now recommend that all metastatic CRC (mCRC) patients should be tested for KRAS and NRAS if anti-EGFR therapy is available [9,10,11]. Only few studies were conducted in low middle income countries due to the high costs related to tumor mutation tests. Our first experience showed no statistically significant relationship between mCRC patient characteristics and KRAS/NRAS mutations. However due to low samples no conclusion has been made. The aim of this study was to report KRAS and NRAS mutation status frequencies in Moroccan patients with mCRC and investigate the associations of these mutations with clinicopathological characteristics in a larger study.

Methods

This study represents the second report of our pilot study in Morocco using the Idylla™ platform: a fully automated, real-time PCR based molecular diagnosis system. Short-term laboratory-based training of technicians for one day only was necessary.

Patients and tumor samples

This is a prospective study where data of consecutive unselected CRC samples were collected from the Laboratory of Pathology at the National Institute of Oncology of Rabat, Morocco, from January 1st 2020 to December 31st 2021. Only patients with confirmed histopathological metastatic CRC were included. Formalin-fixed, paraffin-embedded (FFPE) tumor sections obtained from biopsies or surgical resection were stained with hematoxylin and eosin (H&E). A trained pathologist (YM, MK, SE or BE) confirmed the diagnosis and identified the histological type and differentiation degree of the tumor. He also verified that at least 10% of viable tumor cells were present in every H&E stained slide. If so, each test included one to five 5–10 μm sections of FFPE tissue (5 to 25 μm thickness were needed according to the recommendations for pre-analytical preparation of FFPE samples prior to Idylla™ KRAS and NRAS mutation testing). If not, macrodissection was performed for tumor enrichment. It consists of FFPE tissue manual dissection using scalpel or pipette tip to remove microscopically tumor areas marked by a pathologist on the slide.

KRAS and NRAS mutations analysis

FFPE sections were inserted directly into the Idylla™ platform. Extraction and PCR analysis were performed on the Idylla™ system using cartridges with allele-specific primers that allow qualitative detection of mutations. KRAS and NRAS mutations in codons 12 and 13 of exon 2, 59 and 61 of exon 3 and 117 and 146 of exon 4 were analyzed.

Statistical analysis

The characteristics such as gender, primary tumor site, histological type and degree of tumor differentiation were reported in frequencies. All the continuous variables were reported as mean +/- Standard Deviation (SD) or median with quartiles.

The age was categorized into two categories choosing the cut-off of 60 years old according to the available literature.

The potential associations of KRAS and NRAS mutations with gender, primary tumor site, histological type and degree of differentiation of tumor were analyzed using chi-square (Χ²) test. Tests were considered statistically significant when p value was less than 0.05. All analyses were performed using SPSS 25.0.

Results

Clinicopathological characteristics of patients

Patients.

A total of 414 patients with metastatic CRC were enrolled in this study. 215 (52%) were men and 199 (48%) were women, with a mean age of 59 years ± 16.9 (range 23 to 90 years).

Tumor specimens.

Specimens were from primary tumor (n = 361, 87.2%) or metastases (n = 53, 12.8%) (mainly in liver, peritoneum and lung).

Pathological characteristics.

The rectum was the most frequent site of primary tumor (n = 145, 35%) followed by right-sided colon (n = 94, 22.7%) and sigmoid colon (n = 84, 20.3%). Site was not specified for 3 cases.

Adenocarcinoma not otherwise specified (NOS) was the most frequent histological type (90%). Other subtypes were mucinous adenocarcinoma, poorly cohesive carcinoma and neuroendocrine small cell carcinoma.

Tumors were mostly well or moderately differentiated.

The clinicopathological characteristics of the patients are summarized in Table 1.

Table 1 Clinicopathological features of patients

Mutational status

Analysis was successful in 407 cases (98.3%) for KRAS. Invalid RAS tests were 1.7% for KRAS and 3.1% for NRAS.

KRAS mutation was detected in 51.7% (n = 214/414) of tumors, mainly in codon 12 (78.5%, n = 168). More than 50% of mutations were c.35G > T or c.35G > A (Table 2). These results are concordant to those previously described in the North African population.

Table 2 KRAS mutation status and frequency of mutation types

For NRAS, analysis was successful in 401 cases (96.9%). 94% (389/414) of tumors had wild-type NRAS. NRAS mutation was detected only in 3% (12/414) of cases: codon 61 (8 cases), codon 12 (3 cases) and codon 13 (1 case) (Table 3).

Table 3 NRAS mutation status and frequency of mutation types

Associations between RAS and clinicopathological features

A summary of the main clinicopathological features of KRAS and NRAS mutants and wild-type CRC are shown in Tables 4 and 5.

Table 4 Association between KRAS status and clinicopathological features (n = 407/414)
Table 5 Association between NRAS status and clinicopathological features (n = 401/414)

KRAS and NRAS mutations were more frequent in older patients (56.1% and 5.3% respectively in > 60 years), than in the younger ones (50.8% and 0.5% respectively in ≤ 60 years). For NRAS, the mean age was significantly different between the two groups (p = 0.005). KRAS and NRAS mutations were slightly more common in men than in women (53.8% and 3.4 versus 51.3% and 2.6% respectively). Moreover, KRAS mutations were found more frequently in right-sided (60%) than in left-sided (50.2%) colon cancer, but this did not reach statistical significance (p = 0.08). In contrast, NRAS mutation was more frequent in left-sided colon cancer (3.4% versus 1.9%), but also this did not reach statistical significance (p = 0.44).

KRAS and NRAS mutations were found respectively in 52.9% (190/359) and 3.4% (12/353) of primary tumors and 50% (24/48) and 0% for metastases. These results did not reach statistical significance (p = 0.7 for KRAS and p = 0.19 for NRAS).

For histological type, frequency of KRAS mutation was higher in poorly cohesive carcinoma (75%, n = 3/4), than in other histological types (58.8% in mucinous adenocarcinoma, 51.9% in adenocarcinoma NOS). NRAS mutation was exclusively found in adenocarcinoma, NOS (3.3%, n = 12/360). All these findings did not reach statistical significance (p = 0.79 for KRAS and p = 0.49 for NRAS). KRAS mutation was found more in well and moderately (54.6% and 54.1% respectively) than in poorly differentiated carcinoma (34.3%). NRAS mutation was observed more in well (5.3%) than in moderately (1.8%) differentiated carcinoma. Interestingly, no NRAS mutation was found in poorly differentiated carcinoma (0/35). These findings also did not reach statistical significance (p = 0.21 for KRAS and p = 0.79 for NRAS).

Discussion

This study showed RAS mutation in 54.6% of cases, a low rate of invalid cases despite being a pilot study, significant correlation between NRAS mutation and age and no correlations between RAS mutations and other clinicopathological characteristics.

Previous studies have demonstrated highly variable frequencies of RAS mutations in North Africa ranging from 16 to 75.2% [12,13,14,15,16,17,18,19,20,21,22,23,24,25] (80% for one study but with 20 patients only) [26].

RAS mutation is an early event in colorectal carcinogenesis. In this study, most of tissues (87.20%) were from primary tumor. This high frequency of primary tumor on specimens for RAS study is probably due to habitudes of our institute to not systematically re-biopsy for metastases or rapid progression of disease. Although a high concordance exists between primary CRC and liver and lung metastases [27, 28], metastatic or recurrent CRC tissues are the preferred specimens for RAS (and other biomarkers) testing [29]. Indeed, acquired KRAS mutations during progression of CRC metastases can occur [30]. In absence of metastatic and recurrent CRC tissues, primary tumor tissue is an acceptable alternative [29, 30].

We obtained 20 cases with invalid RAS results: 7 (1.7%) for KRAS and 13 (3.1%) for NRAS. We think that this low rate of invalid cases was achieved through respect to pre-analytical factors: cold ischemia time and formalin fixation. All invalid cases corresponded to prepared outside of the laboratory paraffin blocks. We think that a probable non-optimal pre-analytical phase may have caused irreversible DNA and RNA damage. This made their amplification impossible.

For correlation of primary tumor localization and RAS mutation, literature also was controversial. KRAS was significantly more frequent in left-sided CRC in three studies [20,21,22]. In our study, no correlation between primary tumor site and RAS mutation was observed. Data for association between RAS status and histological type and tumor differentiation were also inconclusive. A summary of frequency and association between RAS status and clinicopathological features in North Africa are shown in Table 6.

Table 6 Frequency and association between RAS status and clinicopathological features in North Africa

Our preliminary results did not show a statistically significant relationship between clinicopathological features and KRAS and NRAS mutations (n = 186) [31]. In the present study, there was a trend towards older patients (> 60 years) for NRAS mutations. Indeed, only one patient with NRAS mutation has ≤ 60 years (n = 1/12).

Worldwide, distribution of RAS mutations is uneven. The KRAS mutation rate is 44.7% in Western Europe, 35.8% in Eastern Europe [32], 41% in Indonesia [33] and 36.1% in China [34] (for Asia) and 19.5% in the Middle East [32]. In many studies, KRAS mutation incidence was higher in right-sided than in left-sided colon tumors [34,35,36] and higher in women [34, 36, 37] but not for NRAS mutation [34, 35]. Other studies did not find differences in location of primary tumor [37, 38] and patients’ gender [38] for KRAS mutation prevalence. Interestingly, KRAS was mutated significantly more often in the primary tumors of patients with lung metastases in one study [27].

This study has several limitations:

1) The small number of samples compared to the published literature from Western countries. However, it represents the largest North African case series.

2) The use of the Idylla™ platform. Indeed, Next Generation Sequencing (NGS) is the current diagnostic gold-standard for RAS mutational analysis in CRC. Several studies have demonstrated that Idylla™ testing is highly accurate with excellent concordance with NGS [39,40,41]. In addition, Idylla™ testing is less than 2 min hands-on time and rapid (2 h) compared with NGS. Costs are lowest for Idylla™ making molecular testing affordable (no molecular pathology platform is needed). This can be very useful for low- and middle-income countries, especially for a small number of cases to test. Our laboratory is in the process of setting up a molecular pathology platform. Our perspective is to retest all 414 specimens with NGS to determine accuracy of our technique.

3) The main objective of the study did not include the analysis of survival and recurrence but this is consistent with this first pilot study of feasibility and assessment of RAS mutations. With more hindsight we will be able to report survival and recurrence of this case series.

Conclusion

We report the largest North African analysis of NRAS and KRAS status in colorectal metastatic patients. This study showed the ability in low middle income countries to perform a high rate of valid tests and the unusual trend towards older patients for NRAS mutations.

Data Availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

CRC:

Colorectal cancer

EGFR:

Epidermal growth factor receptor

RAS:

Rat sarcoma virus

PCR:

Polymerase chain reaction

FFPE:

Formalin-fixed, paraffin-embedded

NOS:

Not otherwise specified

NGS:

Next Generation Sequencing.

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ, Cancer Statistics. 2009. CA: A Cancer Journal for Clinicians. 2009;59:225–49.

  2. Souadka A, Majbar MA, Benkabbou A, Serji B, Souiki T, Bouchentouf SM, et al. Predictive factors of disease-free survival after complete pathological response to neoadjuvant radiotherapy for rectal adenocarcinoma: retrospective case series. BMC Cancer. 2019;19:1008.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Maffeis V, Nicolè L, Cappellesso R, RAS. Cellular Plasticity, and Tumor budding in Colorectal Cancer. Front Oncol. 2019;9:1255.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Prior IA, Lewis PD, Mattos C. A comprehensive survey of ras mutations in cancer. Cancer Res. 2012;72:2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol. 2010;17:1168–76.

    Article  PubMed  Google Scholar 

  6. Winder T, Lenz H-J. Molecular predictive and prognostic markers in colon cancer. Cancer Treat Rev. 2010;36:550–6.

    Article  CAS  PubMed  Google Scholar 

  7. Kawazoe A, Shitara K, Fukuoka S, Kuboki Y, Bando H, Okamoto W, et al. A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in japanese patients with metastatic colorectal cancer. BMC Cancer. 2015;15:258.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal Cancer: a review. JAMA. 2021;325:669–85.

    Article  CAS  PubMed  Google Scholar 

  9. Benson AB III, Venook AP, Al-Hawary MM, Cederquist L, Chen Y-J, Ciombor KK, et al. NCCN Guidelines Insights: Colon cancer, Version 2.2018. J Natl Compr Canc Netw. 2018;16:359–69.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vogel JD, Felder SI, Bhama AR, Hawkins AT, Langenfeld SJ, Shaffer VO, et al. The american society of Colon and rectal Surgeons Clinical Practice Guidelines for the management of Colon cancer. Dis Colon Rectum. 2022;65:148–77.

    Article  PubMed  Google Scholar 

  11. Messersmith WA. NCCN Guidelines updates: management of metastatic colorectal Cancer. J Natl Compr Canc Netw. 2019;17:599–601.

    PubMed  Google Scholar 

  12. El-Serafi MM, Bahnassy AA, Ali NM, Eid SM, Kamel MM, Abdel-Hamid NA, et al. The prognostic value of c-Kit, K-ras codon 12, and p53 codon 72 mutations in egyptian patients with stage II colorectal cancer. Cancer. 2010;116:4954–64.

    Article  CAS  PubMed  Google Scholar 

  13. Bennani B, Gilles S, Fina F, Nanni I, Ibrahimi SA, Riffi AA, et al. Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in moroccan patients with colorectal cancer. Int J Biol Markers. 2010;25:179–84.

    Article  CAS  PubMed  Google Scholar 

  14. Karim B, Florence C, Kamel R, Nadia K, Ines O, Raja M, et al. KRAS mutation detection in tunisian sporadic coloractal cancer patients with direct sequencing, high resolution melting and denaturating high performance liquid chromatography. Cancer Biomarkers. 2011;8:331–40.

    Article  Google Scholar 

  15. Sammoud S, Khiari M, Semeh A, Amine L, Ines C, Amira A, et al. Relationship between expression of ras p21 oncoprotein and mutation status of the K-ras gene in sporadic colorectal cancer patients in Tunisia. Appl Immunohistochem Mol Morphol. 2012;20:146–52.

    Article  CAS  PubMed  Google Scholar 

  16. Kamal MM, Youssef OZ, Lotfy AN, Elsaed ET, Fawzy MMT. Association of folate intake, dietary habits, smoking and COX-2 promotor – 765G > C polymorphism with K-ras mutation in patients with colorectal cancer. J Egypt Natl Canc Inst. 2012;24:115–22.

    Article  PubMed  Google Scholar 

  17. Aissi S, Buisine M-P, Zerimech F, Kourda N, Moussa A, Manai M, et al. KRAS mutations in colorectal cancer from Tunisia: relationships with clinicopathologic variables and data on TP53 mutations and microsatellite instability. Mol Biol Rep. 2013;40:6107–12.

    Article  CAS  PubMed  Google Scholar 

  18. Marchoudi N, Amrani Hassani Joutei H, Jouali F, Fekkak J, Rhaissi H. Distribution of KRAS and BRAF mutations in moroccan patients with advanced colorectal cancer. Pathol Biol (Paris). 2013;61:273–6.

    Article  CAS  PubMed  Google Scholar 

  19. Ines C, Donia O, Rahma B, Ben Ammar A, Sameh A, Khalfallah T, et al. Implication of K-ras and p53 in colorectal cancer carcinogenesis in tunisian population cohort. Tumour Biol. 2014;35:7163–75.

    Article  CAS  PubMed  Google Scholar 

  20. Jouini R, Ferchichi M, BenBrahim E, Ayari I, Khanchel F, Koubaa W, et al. KRAS and NRAS pyrosequencing screening in tunisian colorectal cancer patients in 2015. Heliyon. 2019;5:e01330.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ounissi D, Weslati M, Boughriba R, Hazgui M, Bouraoui S. Clinicopathological characteristics and mutational profile of KRAS and NRAS in tunisian patients with sporadic colorectal cancer. Turk J Med Sci. 2021;51:148–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Agy FE, El agy F, el Bardai S, El Otmani I, Benbrahim Z, Karim IMH, et al. Mutation status and prognostic value of KRAS and NRAS mutations in moroccan colon cancer patients: a first report. PLoS ONE. 2021;16:e0248522.

    Article  PubMed  Google Scholar 

  23. Abudabous A, Drah M, Aldehmani M, Parker I, Alqawi O. KRAS mutations in patients with colorectal cancer in Libya.Molecular and Clinical Oncology. 2021;15.

  24. Asri AE, El Asri A, Ouldim K, Bouguenouch L, Sekal M, Moufid FZ, et al. Dietary Fat Intake and KRAS mutations in Colorectal Cancer in a moroccan Population. Nutrients. 2022;14:318.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Youssef ASE-D, Abdel-Fattah MA, Lotfy MM, Nassar A, Abouelhoda M, Touny AO, et al. Multigene panel sequencing reveals Cancer-specific and common somatic mutations in Colorectal Cancer Patients: an egyptian experience. Curr Issues Mol Biol. 2022;44:1332–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kader AE, Emera Y, Safwat G, Kassem E, Kassem HA. The KRAS StripAssay for detection of KRAS mutation in egyptian patients with colorectal cancer (CRC): a pilot study. J Egypt Natl Cancer Inst. 2013;25:37–41.

    Article  Google Scholar 

  27. Cejas P, López-Gómez M, Aguayo C, Madero R, de Castro Carpeño J, Belda-Iniesta C, et al. KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS ONE. 2009;4:e8199.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O’Dwyer ST, Aziz O. Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine. 2019;40:363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, 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.

    Article  CAS  PubMed  Google Scholar 

  30. Bouchahda M, Karaboué A, Saffroy R, Innominato P, Gorden L, Guettier C, et al. Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis. Cancer Chemother Pharmacol. 2010;66:605–9.

    Article  CAS  PubMed  Google Scholar 

  31. Mounjid C, El Agouri H, Mahdi Y, Laraqui A, Chtati E-N, Ech-charif S, et al. Assessment of KRAS and NRAS status in metastatic colorectal cancer: experience of the National Institute of Oncology in Rabat Morocco. Annals of Cancer Research and Therapy. 2022;30:80–4.

    Article  Google Scholar 

  32. Afrăsânie V-A, 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. Radiol Oncol. 2019;53:265–74.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 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. J Gastrointest Cancer. 2018;49:124–31.

    Article  CAS  PubMed  Google Scholar 

  34. Ye Z, Qiu M, Tang T, Wang F, Zhou Y, Lei M, et al. Gene mutation profiling in chinese colorectal cancer patients and its association with clinicopathological characteristics and prognosis. Cancer Med. 2020;9:745–56.

    Article  CAS  PubMed  Google Scholar 

  35. Bylsma LC, Gillezeau C, Garawin TA, Kelsh MA, Fryzek JP, Sangaré L, et al. Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: a systematic review and meta-analysis. Cancer Med. 2020;9:1044–57.

    Article  PubMed  Google Scholar 

  36. Kwak MS, Cha JM, Cho YH, Kim SH, Yoon JY, Jeon JW, et al. Clinical predictors for KRAS Codon 13 mutations in patients with Colorectal Cancer. J Clin Gastroenterol. 2018;52:431–6.

    Article  CAS  PubMed  Google Scholar 

  37. Shen H, Yuan Y, Hu H-G, Zhong X, Ye X-X, Li M-D, et al. Clinical significance of K-ras and BRAF mutations in chinese colorectal cancer patients. World J Gastroenterol. 2011;17:809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kafatos G, Niepel D, Lowe K, Jenkins-Anderson S, Westhead H, Garawin T, et al. RAS mutation prevalence among patients with metastatic colorectal cancer: a meta-analysis of real-world data. Biomark Med. 2017;11:751–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huang H, Springborn S, Haug K, Bartow K, Samra H, Menon S, et al. Evaluation, validation, and implementation of the Idylla System as Rapid Molecular Testing for Precision Medicine. J Mol Diagn. 2019;21:862–72.

    Article  CAS  PubMed  Google Scholar 

  40. Zekri J, Baghdadi MA, Alardati H, Khallaf H, Kabanja JH. Evaluation of the Idylla KRAS and NRAS mutation test in colorectal cancer tissue. Exp Mol Pathol. 2019;110:104270.

    Article  CAS  PubMed  Google Scholar 

  41. Van Haele M, Vander Borght S, Ceulemans A, Wieërs M, Metsu S, Sagaert X, Weynand B. Rapid clinical mutational testing of KRAS, BRAF and EGFR: a prospective comparative analysis of the Idylla technique with high-throughput next-generation sequencing. J Clin Pathol. 2020;73(1):35–41.

    Article  PubMed  Google Scholar 

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Acknowledgements

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Funding

Declaration.

No funding was received for conducting this study.

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Authors

Contributions

YM analyzed and interpreted the patient data and drafted the manuscript. YM, MK, SE and BE performed the histological examination. BE proposed the study, supervised YM and revised the manuscript. AS, HE and CM have made substantial contributions to analysis and interpretation of patient data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Youssef Mahdi.

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The study was approved by the Human Research Ethics Committee of the University of Mohammed V, Faculty of Medicine and Pharmacy. All patients gave written informed consent before the start of the study. All methods were performed in accordance with the relevant guidelines and regulations.

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Mahdi, Y., Khmou, M., Souadka, A. et al. Correlation between KRAS and NRAS mutational status and clinicopathological features in 414 cases of metastatic colorectal cancer in Morocco: the largest North African case series. BMC Gastroenterol 23, 193 (2023). https://doi.org/10.1186/s12876-023-02694-7

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