Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second most common in females, worldwide (1). CRC incidence has been increasing in Arab countries such as Kuwait and Saudi Arabia (2,3). In Saudi Arabia, the incidence of CRC accounted for 10.4% of all cancers in 2010; it was the most common cancer in males and the third most common in females, after breast and thyroid cancers (4). In the Kuwaiti population, CRC was the most common cancer in males (11.3%) and the second most common in females (9.1%) in 2000–2009 (5). Gene mutation and defective cell regulation are important processes in the development of CRC (6). Accumulation of these mutations, including mutations in KRAS, NRAS, BRAF and PIK3CA, activate multiple signaling pathways, such as RAS-RAF-MAPK and PI3K-PTEN-AKT, that play a major role in regulating cell proliferation, angiogenesis, cell motility and apoptosis (7-9).

Assessment of genetic mutations is an essential element in the modern era of personalized cancer treatment. In the past years, our understanding of some of these mutations and their predictive and prognostic potential has revolutionized the treatment for various malignancies, with improved outcome and patient care [e.g., targeting wild-type RAS in metastatic colon cancer (10), targeting HER2 in gastric adenocarcinoma] (11).

Anti-EGFR medications such as cetuximab and panitumumab are used for treatment of wild-type RAS metastatic CRC, but patients with mutations in the extended RAS family are resistant to these medications. Similarly, the patients with BRAF and the PIK3CA mutation have shown negative response to treatment with EGFR inhibitors (12-18).

The frequency rates of these mutations in CRC differ between populations. Zhang et al. have reported differences in the genetic profiles of KRAS, NRAS, PIK3CA, and BRAF at mutation hotspots between CRC patients from China and those from Western countries. The rate of these mutations in Arab patients with CRC is not well defined (9). The evaluations of the rates of these mutations in Arab population with CRC have been limited to few mutations including KRAS and BRAF (19,20).

The standard definition of the Arab world comprises the 22 countries and territories of the Arab League. The Arab Gulf countries which are also part of the Arab League are: Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain and Oman.

The rate of some mutations of CRC in the Arab population from the Arabian Peninsula has been reported previously. A study by Siraj et al. reported a BRAF mutation rate of 2.5% in a Saudi Arabian population (19).

The rate of KRAS in Arab population from outside the Arab Gulf population has been reported, Elbjeirami et al. reported a KRAS mutation rate of 44% in a Jordanian population (20). The ratio of patients with mutated versus wild-type KRAS in the Jordanian study was similar to that reported in Western countries. Studies from Egypt showed high proportion (35%) of young onset CRC in patients under age 40. The studies also showed distinct KRAS and microsatellite instability (MSI) profiles between young and old CRC patients in Egypt (21,22). DNA methylation was also different in tumors of CRC patients from Egypt, Jordan, and Turkey (23).

The largest study, which included 500 patients from Saudi Arabia, assessed KRAS and BRAF using polymerase chain reaction (PCR) and DNA sequencing; the reported frequency rates were 30.1% and 2.4%, respectively (24). However, no studies have utilized next-generation sequencing (NGS) to assess in-depth mutations in Arab patients with CRC.

In the present study, we aimed to evaluate hotspot mutations by NGS in an Arab population from the Gulf countries with CRC and explored correlations of the mutations with clinicopathological features in this under-studied population.

Methods

Objectives

The primary objective of the study was to determine the frequencies of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC mutations, as well as other somatic mutations, in CRC tumors from 99 Arab patients from the Gulf countries and to compare the results with 99 Western matched patients from our database at MD Anderson Cancer Center and with the frequencies among other populations. The secondary objective was to determine the relationships between these mutations and clinicopathological features of these patients.

Study design

We conducted a retrospective case-case study of Arab-patients from the Gulf countries who were treated in the U.S. at MD Anderson Cancer Center and the Mayo Clinic in Rochester, Minnesota. The electronic databases at both institutions were searched for all patients with a diagnosis of CRC from 2010 to 2014 who had standardized hotspot mutation testing using a 46- or 50-gene multiplex platform by NGS. The electronic records then were searched manually with various criteria to identify patients from the Arabian Peninsula using country of origin, primary language (Arabic), and sponsoring country that covering the medical expenses for the patient and matched Western patients that were treated at MD Anderson Cancer Center. We identified 99 Arab patients with CRC and there were matched (age, sex and type of testing 46- or 50-gene, see below for testing details) with 99 Western patients who had the same testing during the same period. The study was approved by institutional ethics board of MD Anderson Cancer Center (NCT01772771) and Mayo Clinic (15-000563).

Clinicopathological information was abstracted from the medical records for the following variables: age (≤50 or >50 years), sex (male or female), tumor site (right colon, left colon, or rectum), histological type, differentiation, MSI, and TNM stage.

We also conducted a comprehensive literature search for all studies that reported mutation rates in CRC tumors in populations around the world (Middle Eastern, Western, and Asian population). The method of detecting these mutations and the result for each population were recorded. The results were then pooled by region and compared with those from other regions and from our current study population.

Mutations assessments

All the samples (60% primary tumor and 40% other metastatic lesions) were originally evaluated using hematoxylin and eosin staining for tumor cellularity. DNA was extracted, purified, and quantified after hematoxylin and eosin staining. Genomic analysis samples were evaluated using NGS using the Ion AmpliSeq Cancer Panel (Life Technologies, Grand Island, NY, USA) test to assess hotspot mutations in 46 genes (38 patients). Testing later expanded to 50 genes by adding EZH2, IDH2, GNA11, and GNAQ (61 patients). Table S1 lists all tested genes.

Table S1 Codons tested on AmpliSeq 46-gene (CMS46) and 50-gene (CMS50) assays
Full table

Statistical analysis

Fisher’s exact test was used to determine the association between mutation status and clinical factors, as well as the association between markers.

The analysis determined the association between mutation status of each marker (i.e., KRAS, NRAS, BRAF, PIK3CA, TP53, APC) with clinicopathological features, especially histopathological type, tumor differentiation, tumor site, patients’ age, and sex and the association between markers. For all statistical analysis, we used IBM SPSS version 21.0 (IBM Corp., Armonk, NY, USA), and the P value was considered to be significant if it was less than 0.05.

Results

Study population

A total of 198 cases were identified; 99 Arab patients and 99 age- and sex-matched Western patients. Of the 99 Arab patients, 74 (74.7%) patients were from MD Anderson and 25 (25.3%) were from the Mayo Clinic. All of Western patients were treated at MD Anderson Cancer Center. The majority of Arab patients were from Saudi Arabia (38.3%) and the United Arab Emirates (34.3%). The major ethnicity of Western patients were White (79%) followed by Black Afro-American (11%) and Hispanic (10%).

Clinicopathological features

The demographic characteristics and clinicopathological variables for the Arab and Western population are given in Table 1. The mean age of Arab and Western patients was 50.8 and 48.03 years respectively. Of the 99 Arab patients identified, 52.7% had stage IV disease at their initial presentation. Seventy-four point two percent had left-sided tumors including rectum, sigmoid colon and splenic flexure compared to 25.8% had right sided tumors including cecum, hepatic flexure, and transverse colon. Furthermore, the histology of tubular adenocarcinoma (89.2%) was higher than mucinous adenocarcinoma (10.8%). In addition, the percentage of patients with moderately differentiated histology and poorly differentiated histology were 71% and 23.7%, respectively. The clinicopathological variables of the Western population are given in Table 1.

Table 1 Demographic characteristics and clinicopathological variables of 99 Arab patients with colorectal cancer a matched 99 Western patients
Full table

Distribution of KRAS, NRAS, TP53, BRAF, PIK3CA, and APC in the 99 Arab patients with CRC

The rate of mutations in the 99 Arab patients and 99 Western matched patients with CRC using 46-gene (38 patients) and 50-gene (61 patients) panels in each cohort are given in Table 2.

Table 2 The rate of mutations in 99 Arab patients and matched 99 Western cohort with CRC using 46 genes (38 patients) and 50 genes (61 patients) in each cohort
Full table

Of the 4% of Arab patients with NRAS mutation, none had KRAS mutation, in keeping with previous reports that these mutations are mutually exclusive (25). BRAF mutation was found in four Arab patients and was mutually exclusive of KRAS or NRAS mutations. Eight tumors of Arab patients had both KRAS and PIK3CA mutations. PIK3CA mutations were present in 8 (8.1%) Arab patients with KRAS mutations, compared with only 5 Arab patients (5%) with wild-type KRAS. This finding suggests that PIK3CA and KRAS gene mutations represent overlapping subgroups in CRC.

Correlation of gene mutations with clinicopathological findings

A summary of the relationships among the gene mutations and clinicopathological features in Arab CRC patients is provided in Tables 3,4.

Table 3 Correlation between KRAS, NRAS, and BRAF mutation status and clinicopathological features in Arab CRC patients
Full table

Table 4 Correlation between PIK3CA, TP53, and APC mutation status and clinicopathological features in Arab CRC patients
Full table

The associations between KRAS, NRAS, BRAF, PIK3CA, TP53 and APC mutations and Arab population clinicopathological features such as age, gender, family history, personal history of familial adenomatous polyposis (FAP), tumor site, tumor histology, differentiation, and stage were not statistically significant. An exception was a statistically significant association of TP53 mutation with age >50 years (P=0.009). PIK3CA and TP53 were statistically significantly associated with absence of an APC gene mutation (P=0.039 and P=0.04), respectively.

Discussion

Here we present a large retrospective, two-center study that evaluated the frequencies of KRAS, NRAS, BRAF, TP53, APC, and PIK3CA somatic mutations in a cohort of 99 Arab CRC patients. This is the first study that comprehensively evaluated hotspot somatic mutations in Arab patients with CRC.

The majority of the population from the current study was from Saudi Arabia and the United Arab Emirates, however, all the gulf countries share common tribal genetic origin of the population from the Arabian peninsula (26).

Our study utilized comprehensive NGS platform to analyze the mutational profile of Arab CRC patients and assess the frequency. The frequencies of KRAS, NRAS, BRAF, TP53, and APC mutations. We were able to demonstrate similar mutational frequencies to those in most target genes compared with the Western population with the exception; however, PIK3CA which occurred at a lower frequency in the Arab population patients than in Western patients.

We performed a comprehensive literature review for somatic mutations testing in patients with CRC. The total number of cases were 2,981 in Middle Eastern countries (16 studies), 22,441 cases in Western countries (43 studies), and 8,053 in Asian countries (27 studies). Rate of mutations in each study, method of testing, pooled mutation rates based on geographical distribution and total pooled mutation rates from all reported studies to date are summarized in Table 5.

Table 5 Worldwide distribution pattern of KRAS, NRAS, BRAF, PIK3CA, APC, and TP53 mutations
Full table

Wild-type KRAS and NRAS oncogenes encode a family of small proteins with homology to G-proteins that regulate cellular signal transduction (106). The KRAS mutation frequency rate differs throughout the world. Soliman et al. reported that mutation of the KRAS gene was uncommon in Egyptian CRCs in general (11% of patients), in contrast to Western cases (28% in sporadic CRCs), and was only identified in patients older than 40 years (21). The study by Elbjeirami et al. reported KRAS mutation (44%) in a Jordanian population (20). The ratio of patients with mutated versus wild-type KRAS in our current study was similar to that reported in Western countries but differed from Egypt (107), which is a neighboring Middle Eastern country but similar to the Jordanian study (20). Other studies from Saudi Arabia reported rates of KRAS mutation to be 42.2% (108), 28.6% (19), 56% (33), and 30.1% (109). The results of our study are in line with all of the other Arab studies. The data from our study did not show statistical significance between KRAS gene mutation in the Arab population and any covariate such as age or gender, which is consistent with the results of a similar study in a Western population (110). Unlike KRAS mutation frequency rates, NRAS mutation was not previously reported in an Arab population. In Western populations the mutation frequency rates were low; in one study that used NGS, the rate was 5.1% (78). In the present study, NRAS mutation was detected in 4% of Arab patients, which is similar to the Western cohort and consistent with the pooled frequency rates in Asian countries and Western countries (3.6% and 3.8%, respectively).

The BRAF gene encodes a protein that is part of the Ras-Raf-MEK-ERK, or MAPK signaling pathway (111). Activation of this pathway results in cellular growth and proliferation. Siraj et al. reported the frequency of BRAF mutation as 2.5% in 770 Saudi patients. In our study, the BRAF frequency rate was 4% in Arab patients, which is lower than the Western cohort and the estimated frequency in Western countries (9.2%) but similar to the frequency reported in Asian (4.9%) and Middle Eastern countries (4.6%). This difference in BRAF mutational frequency may be attributable to the use of different methods/assays to assess for the mutations. Interestingly, the Western population-based studies reported that BRAF-mutant CRC was significantly more likely to occur in females (108); however, in our study there was no statistically significant association between the BRAF mutation and gender. In contrast to Zhang et al.’s study, which showed a significant association between BRAF mutation and right-sided colon cancer, we did not find any significant association between BRAF mutation and tumor site (9) yet the findings of our study is limited by the small number of patients with BRAF mutation (only four patients).

The PIK3CA gene encodes the catalytic subunit of PI3K, which is an intracellular central mediator of cell survival signals (112). Very few studies describe the frequency of PIK3CA mutations in an Arab population. Abubaker et al. reported a PIK3CA frequency rate of 12.2% in a Saudi population (27), which is consistent with the frequency found in our Arab patients population (13%) and the Western patients cohort (12.1%). However, the frequency rate of PIK3CA mutations in Asian countries (8.5%) appear to be lower compared with Middle Eastern and Western countries. This difference could be attributable to either environmental or genetic factors. Our study found no significant differences between Western and Arab populations with regard to PIK3CA gene mutations and other clinical characteristics (109).

The tumor suppressor gene APC plays an important role in CRC development. Absence of the APC protein leads to accumulation of beta-catenin in the cytoplasm, resulting in constitutive transcriptional activation of TCF-responsive genes, which may contribute to tumor progression (113). The frequency from the pooled results in Middle Eastern countries is (33%), which is consistent with the frequency rate in Asian countries (32.4%), but it is lower than the frequency rate in Western countries (44.8%). In the current study the frequency was (27.3%) in Arab patients and (24.2%) in Western patients. These differences between the frequencies in our population study and pooled frequencies in Middle Eastern countries, Asian countries and Western countries may be attributable to environmental factors.

Loss of TP53 function is one of the major events in the development of CRC. TP53 mutations are thought to occur late in pathogenesis of CRC (39). The TP53 mutation rate in our study was 52% in Arab patients and 47.5% in our Western cohort, which they are significantly higher than the pooled frequency rates encountered in Middle Eastern (38.4%) and Asian countries (40.1%). This difference between our study and the Middle Eastern countries frequency rate may be attributable to different sample selection. Abubaker et al. reported a trend of TP53 mutations towards old age (>50 years old) (27). In the present study, there was a significant association between TP53 mutations and age (>50 years old). This finding is in contrast to previous studies in Western countries (110,114).

Mutations in the FBXW7 gene are thought to impair cyclin E degradation resulting in unchecked cellular growth, and subsequently in progression of CRC (115-117). The frequency of FBXW7 mutation in the present study was 3% in Arab patients, none were found in the matched Western cohort. This is the first report of FBXW7 gene mutation in an Arab population and potential association.

Fleming et al. reported the frequency of SMAD4 mutation in 744 patients with sporadic CRC at 8.6% (118). Mutations in SMAD4 are thought to promote tumorigenesis by allowing CRC cells evade the inhibitory effect of TGF-beta, thus contributing to progression of CRC (119,120). In the present study, the rate of SMAD4 mutation in the Arab patients was 2% where 11.1% in the matched Western cohort. This difference in the frequency rates may be attributable to differences in sample size, ethnicities, and geographical distribution. This is the first report of SMAD4 gene mutation in the Arab population.

EGFR signaling plays a significant role in CRC development and progression. Gene mutations in the EGFR signaling proteins, such as KRAS, NRAS, BRAF, and TP53, are vital factors in evaluating EGFR targeted treatment resistance in patients with CRC (7,107). KRAS-mutant CRC do not respond to anti-EGFR agents such as cetuximab (14). However, only 40–60% of type patients with wild-type KRAS respond to EGFR targeted therapies (121). Therefore, it is very important to identify other molecular alterations that may affect anti-EGFR treatment. De Roock et al. demonstrated that BRAF, NRAS, and PIK3CA mutations affect the anti-EGFR treatment outcome in chemotherapy-resistant metastatic CRC patients (13).

Many environmental factors such as lifestyle and diet are implicated as risk factors for CRC. Subjects consuming a diet rich in meat and fat and poor in fiber have a higher risk for CRC (122-124). Decreased physical activity and obesity also put the subjects in a greater risk for CRC (125,126). Westernization of the developing countries along with changes in diet and lifestyle have been associated with the increasing incidence of CRC in developing countries (127,128). The increased incidence of CRC in Arabian Peninsula is parallel to similar increase incidence of CRC in Westernized countries. The results of the present study report the frequency of KRAS, NRAS, BRAF, TP53, and APC mutations similar to the frequencies in Western population. Many studies have previously indicated that the differences in the incidence of CRC are probably due to environmental and not genetic factors (129). In our study, we found that there was no association between incidence of CRC and clinicopathological factors except the association of TP53 mutation and advanced age. Two studies from Qatar and Jordan have shown associations between CRC and diet with low fiber, sedentary life and obesity in Qatari and Jordanian populations (130,131). A study by Bener et al. evaluated the association of family history, lifestyle and dietary factors with developing CRC in Arab patients. Multivariate stepwise logistic regression analysis showed that family history, BMI, smoking, consuming bakery and soft drinks were significant predictors of development of CRC. Age, gender, a sedentary lifestyle, and being overweight were positively linked with CRC risk (130). Also, there is a recent trend for left-sided CRC in Arabs, probably related to their changing lifestyles (132). All these results may influence CRC screening and diagnostic methodologies with cancer preventive lifestyle recommendations in Arab population.

A possible limitation of current study is the relatively small sample size which, which could potentially limit the generalizability of our findings. We have attempted to decrease this risk by including patients from at least six Arab Gulf countries, which were recruited from two large U.S. institutions.

Conclusions

This is the first study to report comprehensive hotspot somatic mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency but higher rate of FBXW7 mutation. Identification of molecular markers can provide insights into the pathogenic process and help optimize personalized cancer therapy in this poorly studied population.

Acknowledgements

The authors thank Sunita Patterson for providing medical editorial assistance with this article. The study was supported by the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Houston, Texas, USA and Khalifa Bin Zayed Al Nahyan Foundation, Abu Dhabi, United Arab Emirates. Names of the institutions at which the work was performed: MD Anderson Cancer Center; Mayo Clinic, Rochester.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The study was approved by institutional ethics board of MD Anderson Cancer Center (NCT01772771) and Mayo Clinic (15-000563).

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