Colorectal cancer (CRC) is a malignancy originating from the epithelial lining of the colon and rectal mucosa, with significant morbidity and mortality worldwide. In 2020, CRC incidence reached 1.9 million cases with more than 930,000 deaths, and according to Globocan 2022, it ranks fourth in incidence among all cancer types globally and fifth in mortality rate. The disease arises through complex interactions between genetic and environmental factors, including family history, inflammatory bowel disease, lifestyle factors such as obesity, smoking, and dietary patterns, with approximately 90% of new cases occurring in individuals aged over 50 years. ^{1, 2}

Colorectal carcinogenesis is understood as a heterogeneous disease at the genetic level, developing through several pathways including chromosomal instability (CIN), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP) pathway. The CIN pathway is the most common, occurring in 85% of sporadic CRCs, characterized by mutations in oncogenes or tumor suppressor genes such as APC, KRAS, PIK3CA, BRAF, SMAD4, or p53. Among these, KRAS is the most commonly mutated oncogene, occurring in approximately 40% of all CRC cases, resulting in constitutive activation of the KRAS protein which controls intracellular signaling pathways regulating cell proliferation, differentiation, and survival. ^{3, 4}

The American Society of Clinical Oncology recommends that all metastatic CRC patients undergo KRAS gene mutation testing, particularly candidates for anti-EGFR monoclonal antibody therapy. Patients with wild-type KRAS respond well to anti-EGFR therapy, while those with KRAS mutations do not benefit from such treatment. Additionally, KRAS mutation status has prognostic implications, with studies showing that CRC patients with KRAS gene mutations have poorer prognosis. Adenocarcinoma is the most common histopathological finding, occurring in 90% of CRC patients, with some studies suggesting associations between KRAS mutation status and specific histopathological subtypes and tumor locations. ^{5, 6}

Understanding the relationship between KRAS gene mutation status and clinicopathological features is crucial for appropriate management of CRC patients. Previous studies have reported varying associations between KRAS mutations and factors such as age, sex, tumor location, and histological grading, with some indicating that KRAS mutations are more frequent in the proximal colon and associated with mucinous adenocarcinoma. However, these relationships may vary across populations. This study aims to determine the relationship between KRAS gene mutation status and clinicopathological features of CRC patients in Makassar, Indonesia. ^{3, 7}

This study included 33 colorectal adenocarcinoma patients, with the majority aged ≥50 years (75.8%) and male (54.5%), consistent with global epidemiology showing that approximately 90% of new CRC cases occur in patients over 50 years and men have approximately 30% higher risk of developing CRC. ^{3, 8} The frequency of KRAS gene mutations in this study was 42.4% mutant type and 57.6% wild type, aligning with previous reports that KRAS mutations occur in approximately 40% of CRC cases worldwide, though frequencies vary across populations. ^{9, 10} KRAS mutations act as significant oncogenic drivers in colorectal cancer, influencing therapeutic response and prognosis, with mutant type associated with poorer outcomes compared to wild type. ^{11, 12}

Regarding histopathological grading, this study found no significant relationship between KRAS gene mutation status and histological grading (p = 0.607), although patients with KRAS mutant type predominantly had poor differentiated tumors (42.9%) while wild type patients mostly had moderately differentiated tumors (47.4%). While some studies have reported associations between KRAS mutations and poor differentiation, ^{13, 14} our results align with Lee et al. who found no significant difference in differentiation grade between KRAS mutant and wild type in CRC patients. ¹⁶ This lack of association may be due to the heterogeneity of KRAS mutation alleles, as specific mutations such as Q61 have been shown to correlate with poor differentiation, which was not examined in this study. ¹⁴

A significant relationship was found between KRAS mutation status and tumor location (p = 0.040), with KRAS mutant type predominantly located in the right colon (64.3%) and KRAS wild type predominantly in the left colon (73.7%). These findings are consistent with studies reporting that right-sided colon cancers exhibit higher aggressiveness and are associated with distinct carcinogenesis pathways, with higher KRAS mutation frequency in right-sided compared to left-sided tumors. ^{3, 15, 16} Abdelgadir et al. reported that right-sided primary CRC has the highest prevalence of mutated tumors (64%), with specific KRAS mutations showing significantly increased likelihood of right-sided tumors. ¹⁷ The distribution of KRAS mutations predominantly in right-sided tumors occurs through the chromosomal instability pathway, and understanding this relationship can aid early screening and prognosis, as right-sided tumors often remain occult until advanced stages presenting with anemia symptoms, while left-sided tumors tend to cause obstructive symptoms earlier. ^{4, 11}

The association between KRAS mutant type and right-sided tumors aligns with the understanding that tumorigenesis and mutation processes differ based on tumor sidedness, influenced by factors such as diet, genetics, tumor biology, embryological origin, and luminal microenvironment. ¹⁵ This study has limitations including a small sample size, single-center design, and examination of only two clinicopathological aspects (tumor location and histopathological grading) without specific allele analysis. Nevertheless, these findings contribute to the understanding of CRC characteristics in the Indonesian population and support the importance of KRAS mutation testing for therapeutic decision-making, particularly regarding anti-EGFR therapy eligibility. ^{5, 6} Further multicenter studies with larger sample sizes examining additional clinicopathological aspects such as tumor stage and specific mutation alleles are warranted.

Based on research results and discussion, it can be concluded that tumor location is associated with KRAS mutation status (mutant type and wild type), while histopathological grading is not associated with KRAS mutation status (mutant type and wild type). Most KRAS gene mutations (mutant type) are located in right-sided tumors, while KRAS wild type is predominantly located in left-sided tumors.

The study implementation received ethical approval from the Research Ethics Committee on Humans, Faculty of Medicine, Hasanuddin University, Makassar, with letter number 431/UN4.6.4.5.31/PP36/2025.