Variation in the ABC transporter genes and association with clinical outcomes in colorectal cancer: a brief review

ABSTRACT

Colorectal cancer is one of the most prevalent cancers worldwide. We have thus focused on studies on the association of genetic polymorphisms with treatment response and adverse effects in colorectal cancer patients. This review highlights the inter-individual and inter-population genetic variations in ABC transporters and their association with variability in drug response. Several studies report the association of specific ABC transporter gene polymorphisms with the risk of developing colorectal carcinoma and the clinical outcomes in patients undergoing chemotherapy. It is important to understand genetic polymorphisms and genetic profiling for colorectal cancer patients in the context of personalized medication. This review is built on a comprehensive knowledge of the pharmacogenetics of colorectal carcinoma with a special focus on ABC polymorphism.

1. Introduction

Focused research on the pharmacogenetics of human cancers is a growing trend globally as the mortality rate with cancers has surpassed various communicable diseases like AIDS, tuberculosis, and malaria [1]. The burden is expected to increase further by 2040 [1]. Colorectal cancer (CRC) holds the third position out of the most frequently diagnosed cancers and is one of the leading causes of cancer-related deaths worldwide [2]. Surprisingly, more than half of the deaths with colorectal cancer are attributable to risk factors related to unhealthy lifestyles [2]. These factors include smoking, alcohol abuse, consumption of unhealthy diets, sedentary lifestyle, and obesity [3]. The high mortality rate is surmountable if regular screening and surveillance of high-risk patients is considered a regular practice in healthcare institutions worldwide. According to the statistics published in 2020 by GLOBOCAN, the worldwide prevalence of colorectal cancer is 10% among cancers making it the third most common type of cancer, after breast cancer and lung cancer [4]. Colorectal cancer is the carcinoma of the colon or rectum, both of which are parts of large intestines. The disease is characterized by the uncontrolled growth of cells of aforementioned region ultimately leading to the formation of a mass or tumor [5]. Occasionally, an incidental growth of a polyp can also lead to progression into a tumor. The disease is more common in males aged around 50 years [6]. Genetic predisposition also plays an integral role in the determination of disease-specific parameters [6]. A colonoscopy followed by tissue biopsy remains the mainstay of diagnosis so far. Moreover, fecal occult blood test (FOBT) along with colonoscopy and sigmoidoscopy is used for colorectal cancer screening worldwide [7]. Colorectal cancer commonly presents as altered bowel habits and a mass or growth on digital rectal examination [8]. The patient might report persistent diarrhea or constipation as their very first complaint. Moreover, bleeding per rectum and anemia can also lead to a suspicious diagnosis and are followed by a colonoscopy for a definite diagnosis. Advanced stages of undiagnosed cancer can appear as abnormal functioning of other organs like the liver and lungs [9]. The early stages of the disease are characterized by the involvement of intestinal mucosa and submucosa while subsequent stages show involvement of lymph nodes and distant organs (metastases) [10]. Upon colonoscopy, the gross appearance of the disease is described as ulceration, uplift, or infiltration of cancerous tissue. Staging is an important determinant of disease prognosis and selection of treatment modality [10]. The disease can metastasize through local invasion, lymphatic metastases, hematogenous metastases, or implantation metastases [10]. More than 60 % of metastases take place through the lymphatic route. Hematogenous metastases are the main cause of the spread of disease to the lungs and liver.

2. Pathophysiology

Genetic mutations which may be somatic or germline are considered to be an important determinant in the pathophysiology of colorectal carcinoma [11]. These mutations often lead to transformation of a healthy colonic epithelium to an adenoma initially followed by an invasive carcinoma later (Figure 1). The pathology involves uncontrolled proliferation of epithelial cells which leads to invasion of surrounding structures and ultimately metastases to the lungs, liver, and brain. Clinical evidence suggests that colorectal carcinomas mostly arise from the dysplastic changes of adenomatous polyps over a decade [12]. These changes ultimately progress to the invasive form of the disease. Common pathways at molecular levels explored to date include chromosomal instability, abnormalities in mismatch repair, hypermethylation of DNA, and histone modification [13]. Chromosomal instability is characterized by an imbalance between the equilibrium of oncogenes and tumor suppressor genes. Similarly, abnormalities in mismatch repair led to the accumulation of errors within the genome leading to serious microsatellite and microtubular instability [14]. DNA hypermethylation further leads to either activation or deactivation of various genes. Sporadic mutations of RAS (Rat sarcoma) oncogene leading to uncontrolled division of epithelial cells have also been implicated as a common underlying pathology of colorectal carcinoma [15]. Other genes with linkage to disease pathology include APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), P53, K-RAS (Kirsten rat sarcoma), C-MYC (cellular myc), BRAF and MCC (colorectal mutant cancer protein) [16]. Recently mutations in cyclooxygenase and peroxisome proliferator – activating receptor genes have been explored to have a cardinal role in colorectal tumorigenesis. More than 90% of the cancers among colorectal cancers are adenocarcinomas [17].

Figure 1.

Risk factors and mutations associated with the pathogenesis of colorectal cancer.

3. Current treatment strategies

The disease is managed by either of the three management approaches; surgery, chemotherapy, and radiotherapy depending upon the patient profile and stage of the cancer [2]. Surgical resection is reserved for patients with non-metastatic localized disease mostly diagnosed as stage I cancer. Chemotherapy can be initiated before surgery (neoadjuvant), after surgery (adjuvant), or maybe the sole treatment of the disease (palliative) when surgery is not an option [18]. Common chemotherapeutic drugs used for the treatment of colorectal cancer include 5-fluorouracil (5-FU), irinotecan, capecitabine, and platinum analogues with 5-FU being the first line and most commonly used drug [19]. The response to these drugs varies from patient to patient with some patients responding satisfactorily to the treatment and others not responding at all [4]. The variation in these responses has been related to genetic polymorphism associated with proteins involved in the transport, metabolism and excretion of these drugs. This polymorphism has contributed to the idea of personalized medication and genetic profiling for each patient.

4. An insight into the variable treatment response and genetic polymorphism

Colorectal cancer is a heterogeneous disease that involves numerous metabolic pathways. Several genes are involved in various manifestations of the disease. The interplay of genetic and epigenetic factors is the mainstay of variable responses and variable progression of the disease [5]. Mutations in APC, p53, and KRAS are implicated in the majority of cases however many other genes are involved as well in a small number of cases leading to a heterogenetic profile of the disease [20]. Various differences have been observed in the prognosis and disease presentation of hypermutated and non-mutated individuals. Recent studies have also highlighted the role of genetic and specifically single nucleotide polymorphisms (SNPs) in association with the risk of development of disease and its response to treatment [7]. Genetic polymorphisms are defined as alterations in heritable sequence of genome appearing in more than 1% of the human population which can lead to modification of gene expression and function [7]. This leads to variations in disease pathways as well as outcomes of diseases. SNPs are present constantly in the human genome and are repeated after every 1900 base pairs except in sex chromosomes [8]. SNPs may increase or decrease the susceptibility of a disease. In recent years, various molecular genetic studies on different populations have hypothesized the importance of genetic polymorphisms in the outcome of various diseases including colorectal carcinoma. Exploration of cytochrome p-450 (CYP), ATP-binding cassette transporters (ABC), and Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism through a bundle of studies has significantly supported the hypothesis of genetic polymorphism and its relation to disease progression and future in colorectal cancer patients [9].

CYP enzymes, particularly CYP3A4 and CYP2C9, influence the metabolism of drugs like irinotecan and capecitabine, which are pivotal in CRC therapy. Polymorphisms in these enzymes can lead to altered drug levels, impacting both toxicity and therapeutic efficacy, thereby indirectly affecting disease progression [10].

Likewise, UGT1A1 polymorphism, especially UGT1A1 28 and 6 alleles, affects glucuronidation of SN-38, the active metabolite of irinotecan. Reduced glucuronidation leads to higher SN-38 levels, increasing risk of toxicity, but potentially improving tumor response and impacting survival outcomes [9]. Hence, both gene families play a role in clinical outcomes beyond drug metabolism.

Certain ABC polymorphisms show significant interethnic variation. For example, the ABCG2 rs2231142 variant allele (421A) is more prevalent in East Asian populations (~30%) compared to Europeans (~10%) and Africans ( < 5%) gnomAD and 1000 Genomes database [12]. Similarly, ABCB1 C.3435C > T (rs1045642) and G2677T/A polymorphisms have been shown to be more frequent in East Asian and South Asian cohorts. This inter-population variability can influence drug response and adverse events across different ethnic groups.

The molecular impact of ABC transporter SNPs includes alterations in gene expression, ATP-binding activity, efflux capacity, and cellular localization. For example, the synonymous ABCB1 c.3435C > T (rs1045642) variant is associated with reduced P-glycoprotein (P-gp) expression due to altered mRNA folding and stability [12]. Similarly, ABCG2 c.421C > A (rs2231142) leads to a Q141K amino acid substitution, impairing ATPase activity, protein folding, and efflux function, thereby increasing intracellular drug accumulation [12]. These mechanisms underlie the pharmacokinetic variability and adverse event profiles associated with several chemotherapeutic agents used in CRC.

5. Role of ABC transporters in colorectal chemotherapy

ATP-binding cassette transporters are a family of proteins often abbreviated as ABC transporters. This group encompasses major and minor transmembrane macromolecules which are involved in the transport of various cellular components like ions, amino acids, lipids, sugars, anti-oxidants, hormones, vitamins, leukotrienes, prostaglandins, xenobiotics, drugs across the cell membrane [13]. This action is mediated through the utilization of ATP molecules. There are seven subfamilies of ABC transporters characterized from A to G and thus 48 ABC transporters have been identified in humans [15]. ABC transporters vary in their specificity as some can transport a wide variety of substances while some of them are restricted to specific substrates only [15]. Importantly drugs used in the treatment of cancers specifically colorectal cancer are transported out of the cell mainly through ABC transporters thus they are important predictors of drug response and resistance. ABC transporters exhibit a plethora of inter-individual and inter population genetic variations [11]. The association of this family of proteins with variability seen in the pharmacokinetic properties of drugs used in the treatment of colorectal cancer has been established in numerous studies. Variable degree of drug response is seen in association with variability in the expression of ABC transporters in cancer patients undergoing chemotherapy like drug disposition and efficacy of chemotherapeutic drugs [21]. All seven families of the ABC transporter gene have cardinal roles in chemotherapeutic responses [22]. Each family is involved in the accumulation of lipids in a wide variety of cells. Members of this family are also involved in the sequestration of drugs in subcellular compartments thus leading to chemoresistance. Moreover, numerous studies have implicated their role in multi-drug resistance to cancer chemotherapy. This review thus highlights the association of ABC polymorphism with variable clinical outcomes seen in colorectal cancer patients undergoing cancer chemotherapy.

6. Association of ABC transporter expression with treatment response in pre-clinical studies

Sapitinib was scrutinized for reversing the resistance against paclitaxel and doxorubicin treatment [23]. Sapitinib is an inhibitor of epidermal growth factor and is used in the treatment of various human cancers. This study made use of SW620/Ad300, HEK293/ABCB1 colorectal cell lines. SW620 is a parental cell line while SW620/Ad300 and HEK293/ABCB1 cell lines express ABCB1 transporter. Sapitinib increased the efficacy of both the anti-cancer drugs in ABCB1 overexpressing cells significantly without changing the genetic expression or the subcellular location of this transporter. Furthermore, Sapitinib, increased the intracellular concentration of paclitaxel in SW620/AD300 cell lines. This change was exhibited as a result of π-π hydrogen bond interaction between Sapitinib and the efflux site of the ABCB1 transporter. Liu and colleagues assessed the efficacy of gedatolisib with reference to resistance against the drug in ABC overexpressing cell lines [24]. The role of two ABC transporter types namely ABCB1 and ABCG2 in resistance to gedatosilib was explored using Western blot and immunofluorescence assays. Moreover, the effect of gedatolisib on the ATPase activity of both these transporters was assessed. The study majorly recruited the cell viability assay of colorectal cancer cells for its findings. The study suggested that if overexpressed, ABCB1 and ABCG2 can restrict the clinical efficacy of gedatolisib in colorectal cell lines, and the inhibitors of these transporters can have a role in improving the resistance against treatment. A rodent-based study elucidating resistance pathways found that several molecular pathways conferred resistance to oxaliplatin-based on their ABC polymorphisms [25]. The study included ABCB1 and ABCC2 as key molecular targets. Hence it was established that certain polymorphisms in ATP-binding proteins can inhibit ABC transporter, alter the oxaliplatin resistance, and reduce the adverse effects of treatment. The clinical efficacy of a Chinese medication Gegen Qinlian Decoction (GQD) against oxaliplatin resistant cells was also explored in this study. It was found that GQD decreases the mRNA expression of ABCB1, ABCC2, and ABCG2 which leads to decreased resistance to oxaliplatin therapy further highlighting the role of this specific gene and its polymorphism in colorectal chemotherapy. An investigational study on Colo-25 cells lines had shown that cells with overexpression of ABC transporters particularly ABCG1 transporter were chemo-resistant [15]. These Colo-25 cells with high levels of ABCG1 transporter had poor prognosis as well. Furthermore, the study identified a novel mechanism where Hedgehog-GLI (HH-GLI) signaling regulated the resistance to chemotherapy in colorectal cancer cell lines as GLI has potential binding sites on the promoter regions of six major families of ABC transporter. A direct functional link was established between the HH-GLI pathway and ABC transporter genes as inhibition of this pathway led to reduced upregulation of ABC transporter and thus reduced chemoresistance. The interplay of this pathway and ABC genes was seen to be directly related to poor prognosis of disease according to this study. VKNG-2, a novel benzamide derivative, is a potent small-molecule inhibitor of the ABCG2 transporter. It reverses multidrug resistance by inhibiting the efflux of chemotherapeutic agents like mitoxantrone in ABCG2-overexpressing colon cancer cells. The dependence of VKNG-2 efficacy on the expression of ABCG2 also provides another insight to the validation of above-mentioned facts [26]. S1-M1-80 colon cancer cell line was used in this study which has a high expression of ABCG2 transporter. It was thus established in this in-vitro study that VKNG-2 reverses the multi-drug resistance of S1-M1-80 to mitoxantrone by inhibition of ABCG2 transporter which is involved in the efflux of mitoxantrone.

7. Association with treatment response in clinical studies

ABC polymorphism had a prognostic role in treatment with irinotecan (FOLFIRI) in a clinical trial of 250 patients of metastatic colorectal cancer [27]. The clinical outcome was assessed based on response rate which was classified as partial or complete response, survival, and progression time. Polymorphism functional analysis was performed by collecting pharmacokinetic data of 71 patients. At the end of the study, two variants of the ABCB1 gene (rs2032582, rs7699188) were found as important determinants of response rate. Another major finding was that patients with ABCB1 c.2677 G > T/A (rs2032582) polymorphism had a better overall survival rate. However, these variants were not associated with any difference in pharmacokinetic parameters. The study established that ABC polymorphism was associated with the outcome of the FOLFIRI regime. Another study found the ABCC2 genetic variant (rs717620) an important determinant of therapy in colorectal cancers in Thai patients. The role of ABCC2 and solute carrier organic anion transporter family member 1B1 (SLCO1B1) polymorphism in relation to irinotecan therapy was explored in 49 Thai colorectal cancer patients for a period of 6 months. After performing the genotyping analysis of ABCC2 (C > T, rs717620) and SLCO1B1 c.388A > G (rs2306283), the treatment responses were evaluated. The combined genotypes of ABCC2 and SLCO1B1 were associated with clinical benefits. All the patients with at least one variant allele of SLCO1B1 and ABCC2 combined were either in partial response or stable disease group while patients with other genotypes had progressive disease in this population. This study hence postulated the combined effect of ABCC2 and SLCO1B1 polymorphisms to be associated with better clinical outcomes in response to irinotecan treatment [28]. The role of ABCB1 polymorphism in determining the cancer chemotherapy response to colorectal patients was also validated in a case-control study performed on the C3435T, C1236T, and G2677T/A polymorphisms in the ABCB1 gene. The study recruited 1028 colorectal cancer patients and 1230 controls. It was observed that ABCB1 C.3435C > T (rs1045642) and G2677T/A variants increased the risk of developing colorectal cancer in Chinese population. The ABCB1 C.3435C > T (rs1045642) CT genotype had a significant effect on the time to recurrence. Patients who carried ABCB1 C1236T variants exhibited a relatively longer postoperative survival rate after oxaliplatin-based chemotherapy. Moreover,1236TT–2677TT–3435TT haplotype carriers had poor progression-free and recurrence-free survival [29]. Oxaliplatin is frequently used with 5-fluorouracil in colorectal cancer treatment. The eventual bioavailability of oxaliplatin is based on transporter enzymes. Genetic variation in these enzymes can lead to variable responses to oxaliplatin. The role of ABC transporters in oxaliplatin-based chemotherapy was further assessed in relation to two SNPs in the ABCG2 (rs2231142 and rs2622621) gene, especially concerning disease prognosis and treatment response. The study comprised data from 580 patients with colorectal cancer. At the end of this study, better disease-free survival and overall survival were seen in ABCG2 rs2231142CA/AA carriers. On the contrary, the ABCG2 rs2622621 CG/GG genotype was associated with poor prognostic outcomes in terms of disease-free and overall survival. Hence the study established the propensity of the ABC gene to have a cardinal role in terms of response to chemotherapy [29]. An improvement of 3.7% in predicting oxaliplatin treatment and ABCC10 rs2125739 association with decreased risk of death was observed in a clinical study involving the German population, in which 1444 SNPs from metabolic and transporter pathways for oxaliplatin were investigated. This study used 623 stage II-IV CRC patients. Out of this cohort, 201 patients were prescribed oxaliplatin. Nine genes having different association with overall survival in response to oxaliplatin were selected. Model selection resulted in the inclusion of six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, and ATP8B3. Several variants or SNPs in transport genes were found to be predictive markers for oxaliplatin therapy in colorectal cancer patients [30]. The dosage recommendation for capecitabine (CAP) in combination with oxaliplatin was recommended when variation in pharmacokinetic and pharmacodynamic properties of CAP and its metabolites was explored in a clinical trial with reference to different polymorphisms of the ABC gene (Table 1). This study recruited 48 patients with colorectal cancer. Approximately 432 samples of plasma levels of CAP and its metabolites 5´-desoxi-5 fluorouridine (5´-DFUR) and 5-fluorouracil (5-FU), were analyzed. The dose of CAP was kept in a range of 1250 to 2500 mg/m2/24 h. Plasma levels of CAP, 5´-DFUR, and 5-FU were measured at 1, 2, and 3 hours after administration. The rs6720173 SNP of the ABCG5 gene improved clearance of 5´-DFUR by 182% and the rs2271862 SNP of the ABCA2 gene improved clearance of 5-FU by 184%. The study proposed dosage recommendation for CAP in combination with oxaliplatin as ≤1750 mg/m2/24 h for mutated allele and ≤600 mg/m2/24 h in patients with wild allele for SNP rs2271862. In the case of monotherapy, a dose of ≤ 3000 and ≤2400 mg/m2/24 h in patients with mutated and wild alleles for single nucleotide polymorphisms rs2271862 was proposed [31]. Although 5-fluorouracil (5-FU) is primarily metabolized by the enzyme dihydropyrimidine dehydrogenase (DPYD), its intracellular concentration and resistance can also be modulated by ABC transporters such as ABCC5 and ABCG2. Recent studies suggest that ABCG2 polymorphisms may influence 5-FU pharmacokinetics and toxicity, especially in combination regimens like CAPOX or FOLFIRI [27]. For instance, ABCG2 rs2231142 was associated with altered clearance of 5-FU metabolites [31]. Additionally, reduced function alleles may impair drug efflux, leading to increased toxicity or improved efficacy depending on tumor expression profiles.

Table 1.

Various ABC polymorphisms and their effects in response to chemotherapy for colorectal cancers.

Gene	SNPs	Sample size	Population	Drug	Effect/association	Reference
ABCG2 ABCB1	−15622C > T rs7699188 rs2032582	250	White	Irinotecan	Better response rate Better response rate Improved overall survival rate	[27]
ABCC2	rs717620	49	Thai	Irinotecan	Better survival rate in case of combined ABCC2 and SLCO1B1 genotype	[28]
ABCB1	C3435T C1236T	1028 cases, 1230 controls	Chinese	Oxaliplatin	Significant effect on time to recurrence Longer postoperative survival rate	[29]
ABCG2	rs2231142CA/AA rs2622621CG/GG	580	Chinese	Oxaliplatin	Better disease-free survival and overall survival Poor prognostic outcome	[35]
ABCA9 ABCB11 ABCC10	rs1860447 rs2287618 rs3770591 rs853778 rs2125739	201	German	Oxaliplatin	Insignificant outcome Insignificant results Decreased risk of death	[30]
ABCG5 ABCA2	rs2125739 rs2271862	48	Caucasian	Capacetabine	Better clearance of metabolites Better clearance of metabolites	[31]

8. Association with the adverse effects in colorectal cancer patients

Genetic variants in several ABC genes are associated with a lower frequency of capecitabine induced neutropenia. A recent prospective study carried out on stage II and III colorectal cancer patients in Japan investigated the role of ABCA2, ABCG5, and ABCB1 gene polymorphism on Capecitabine-oxaliplatin (Cape Ox) combination pharmacokinetics and toxicity [32]. ABCA2 rs2271862, ABCG5 rs6720173 and ABCB1 rs1128503, rs2032582, and rs1045642 SNPs were analyzed. Their results showed that ABCA2 rs2271862 TT genotype was significantly associated with lower dose requirement and lower frequency of capecitabine-induced neutropenia. There was no association between ABCG5 rs6720173 and the pharmacokinetics or toxicities of capecitabine. A recent prospective study in Japanese stage II – III colorectal cancer patients investigated polymorphisms in ABCA2 (c.4544 G > A, rs2271862), ABCG5 (c.1416C > T, rs6720173), and ABCB1 (rs1128503, rs2032582, and rs1045642) and ABCG2 (c.421C > A, rs2231142) to assess their role in capecitabine-oxaliplatin pharmacokinetics and toxicity. No significant associations were seen for ABCG2 SNPs. The minor allele ABCG2 was found associated with a lower incidence of irinotecan adverse effects in a cohort of colorectal cancer patients in North Israel [33]. The investigated genetic variants included ABCG2 rs2231142, ABCB1 rs1045642, and ABCC2 rs3740066, which were studied in 601 patients of colorectal cancer who received irinotecan. A composite product was formulated for adverse effects like hematological disturbances, gastrointestinal disturbances, and mortality. The variant allele (A) of ABCG2 had a lower incidence of irinotecan adverse effects while ABCB1 and ABCC2 had no association with the incidence or severity of adverse effects. The variant allele (A) was prevalent in 13.6% of the cohort (601 CRC patients) and it was established that this minor allele of rs2231142 in the efflux transporter gene ABCG2 offered protection against serious adverse effects in patients of colorectal cancer treated with irinotecan. Diarrhea is one of the most common side effects encountered in patients being treated with irinotecan for colorectal cancer [3]. An exploratory analysis for the evaluation of this specific toxicity of irinotecan in relation to ABCC2 polymorphism revealed that the ABCC2 −1549 G > A rs2273697, and −1249 G > A SNP had variable adverse effect presentation in the patients. More than 53% patients involved in the study experienced diarrhea out of which grade III and grade IV diarrhea was more frequently associated with the AA genotype of ABCC2 −1549 G > A (rs2273697). Some studies have suggested that ABC genetic variants may be associated with irinotecan induced severe neutropenia. A study on 66 CRC patients in the Thai population [10] investigated the association of genetic variations in ABCC2, ABCB1, and various other genes to irinotecan-induced toxicity. Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, were 0.67, 0.43, 0.23 and 0.27 respectively. Toxicities were assessed after the first and second cycles of irinotecan treatment. The patients with genotype ABCC2 c.3972C > T had significantly shown grade 1–4 neutropenia at the first cycle of irinotecan therapy. As a result, this study concluded that ABCC2 rs3740066c.3972C > T might be associated with irinotecan-induced severe neutropenia. Peripheral neurotoxicity is the dose-limiting toxicity of oxaliplatin treatment in colorectal carcinoma patients. Nichetti and colleagues reported a slight association of the ABC gene polymorphisms with oxaliplatin-induced peripheral toxicity (Table 2). The data was acquired from 120 CRC patients from 2010 to 2016 [34]. SNPs in ABC transporters lead to high levels of oxaliplatin within the cells of dorsal root ganglia and thus lead to peripheral neurotoxicity. In this study, SNPs of ABC transporters like ABCC2 (−24C > T/rs717620 and c.4544 G > A(rs8187710), ABCG2 c.421 C > A/(rs2231142), ABCB1 c.3435 C > T(rs1045642) were evaluated alongside SLC31A1 c. −36 + 2451 T > G(rs10981694) for their association with grade 2–3 peripheral neurotoxicity in metastatic colorectal carcinoma patients under oxaliplatin therapy. The dominant model of heterozygous and homozygous SNPs was considered and found that a slight association of these polymorphisms with oxaliplatin-induced peripheral toxicity exists (Table 3).

Table 2.

Various ABC polymorphisms and association with adverse effects in response to chemotherapy for colorectal cancers.

Gene	SNPs	Sample size	Population	Drug	Effect/association	Reference
ABCA2	rs2271862	37	Japanese	Capecitabine	Low dose requirement Lower frequency of neutropenia (grade 2)	[32]
ABCG2 ABCB1 ABCC2	rs2231142 rs1045642 rs3740066	601	North Israel	Irinotecan	Lower incidence of adverse effects No effect No effect	[33]
ABCC2	rs2273697	75	United States	Irinotecan	Association with diarrhea	[3]
ABCC2 ABCG2 ABCB1	c.3972C > T rs3740066 c.421C > A rs2231142 c.1236C > T rs1128503 c.3435C > T rs1045642	66	Thai	Irinotecan	Association with severe neutropenia No association No association No association	[10]
ABCB1 ABCC2 ABCG2	c.3435 C > T rs1045642 −24C > T rs717620 c.421 C > A rs2231142	120	Italian	Oxaliplatin	Association with peripheral neurotoxicity Association with peripheral neurotoxicity Association with peripheral neurotoxicity	[34]

Table 3.

Summarizing drug-SNP specificity.

SNP (Gene)	Drug(s)	Impact	Specificity
ABCB1 c.3435C > T (rs1045642)	Irinotecan, Oxaliplatin	↓ Transporter expression	Multi-drug
ABCB1 c.2677 G > T/A (rs2032582)	Irinotecan	Altered substrate specificity	Irinotecan
ABCG2 c.421C > A (rs2231142)	Irinotecan, 5-FU	↓ Efflux function, ↑ toxicity	Multi-drug
ABCA2 c.4544 G > A (rs2271862)	Capecitabine	↑ Clearance	Capecitabine
ABCC2 −1549 G > A (rs2273697)	Irinotecan	↑ GI toxicity	Irinotecan

The listed SNPs were curated from previously published clinical and preclinical studies. While no independent analysis was performed, population-level allele frequencies and pharmacogenomic relevance were cross-referenced using PharmGKB, Ensembl, and the 1000 Genomes Project where appropriate to contextualize population variability and functional impact.

9. Future perspectives

Colorectal cancer ranks as the third most frequently diagnosed cancer, a prevalence largely attributed to a combination of genetic and environmental factors [4]. Genetic mutations stand out as primary contributors to colorectal cancer worldwide [11]. These mutations, alongside a multitude of factors, have significantly heightened resistance to chemotherapy over recent decades. Consequently, research has pivoted toward gene-specific therapies and personalized medicine, underscoring the imperative to explore genetic polymorphisms in relation to drug responses [1]. Given the heterogeneous nature of colorectal cancer, chemotherapy responses vary among patients due to genetic polymorphisms affecting proteins crucial for drug transport, metabolism, and excretion [4]. The evidence from preclinical and clinical studies support for the pharmacogenetic profiling of CRC patients for ABC genetic variants. For example, several preclinical studies have utilized colorectal cell lines or animal models to investigate ABC polymorphisms such as ABCB1 c.3435C > T (rs1045642), ABCB1 c.2677 G > T/A (rs2032582), and ABCG2 c.421C > A (rs2231142) in relation to the efficacy of novel agents like sapitinib, gedatolisib, and VKNG-2. For instance, the drug Sapitinib augmented the effectiveness of paclitaxel and doxorubicin in ABCB1-overexpressing cells. This affirms the notion that ABC transporters play pivotal roles in the efficacy, toxicity, and resistance of anticancer therapy SNPs in ABC transporters can alter their function, leading to changes in drug efflux which can result in drug resistance. This fact was especially evident in studies where ABCG1 overexpression correlated with chemoresistance in Colo-25 lines, leading to poorer prognosis, whereas inhibition of ABCG2 by VKNG-2 reversed multidrug resistance in the S1-M1-80 cell line [26]. The reduction of mRNA expression of ABCB1, ABCC2, and ABCG2 decreases resistance to oxaliplatin therapy further highlighting the role of this of specific ABCB1 and ABCG2 polymorphisms, such as ABCB1 c.3435C > T and ABCG2 c.421C > A, which have been shown to affect transporter expression or function and thereby influence clinical outcomes [10]. The importance of the role of ABS transporters in the prognosis of CRC is highlighted by several studies including FOLFIRI- a clinical trial of 250 patients. Importantly patients with ABCB1 rs2032582 polymorphism had better overall survival rate. On the contrary, ABCG2 rs2622621 CG/GG genotype was associated with poor prognostic outcome in terms of disease-free and overall survival in another study [35]. Several studies have delved into the correlation between ABC gene polymorphisms and the efficacy of anticancer drug therapies, particularly focusing on drugs like capecitabine, irinotecan, and oxaliplatin which are commonly employed in colorectal cancer treatment [13]. Other studies have examined the impact of ABC gene polymorphisms on the pharmacokinetics and toxicity of chemotherapy in colorectal cancer (CRC) patients. ABCA2 rs2271862 TT genotype correlated with reduced capecitabine dose requirements and lower neutropenia frequency [32]. Similarly, Barnett-Griness, et al. [33] observed that the minor allele of ABCG2 rs2231142 offered protection against irinotecan adverse effects. However, Aoullay, et al. [3] found ABCC2 rs2273697 and rs3740066 associated with diarrhea and severe neutropenia, respectively. Atasilp, et al. [10] linked ABCC2 c.3972C > T genotype with irinotecan-induced neutropenia. Lastly, Nichetti, et al. [34] explored ABC transporter SNPs’ association with oxaliplatin-induced peripheral neurotoxicity, noting a modest correlation. These findings collectively emphasize the role of ABC transporter polymorphisms in modulating chemotherapy outcomes. For example, ABCA2 c.4544 G > A (rs2271862) has been associated with increased clearance of 5-FU, suggesting that patients with the variant allele may require higher doses of capecitabine. In contrast, carriers of the ABCB1 c.3435T allele (rs1045642) may exhibit decreased expression of the transporter, possibly benefiting from lower doses to avoid toxicity due to reduced drug efflux [31,32]. These examples highlight the potential for genotype-guided dosing strategies. The dose of the drugs may also be adjusted based on the genetic variants in ABC genes [31]. This study added the dynamics to implications of polymorphisms in the ABC transporter gene. Knowledge of ABC polymorphisms can serve as a guide to personalized treatment strategies in colorectal cancer. Clinicians may consider genetic testing for ABC polymorphisms to guide drug selection, dosing, and treatment regimens tailored to each patient’s genetic profile. For instance, certain ABC polymorphisms result in increased drug efflux or reduced intracellular drug retention, which may mimic a decreased uptake effect. Although ABC transporters are efflux pumps, certain variants (e.g., ABCG2 c.421C > A) reduce transporter activity, thereby increasing intracellular drug levels, while others (e.g., ABCB1 c.2677T) enhance efflux, leading to subtherapeutic drug exposure may benefit from alternative chemotherapy agents or dosage adjustments to optimize treatment outcomes while minimizing toxicity [11]. As discussed above, an additional significant implication of identifying single nucleotide polymorphisms (SNPs) lies in their potential to pinpoint patients more likely to benefit from chemotherapeutic drugs, either individually or in combination. While ABC transporter genotyping is not yet widely implemented in clinical oncology guidelines, some SNPs such as UGT1A1 *28 (related to irinotecan dosing) have been included in CPIC guidelines. ABCG2 rs2231142 and ABCB1 rs1045642 are present in certain commercial pharmacogenetic panels (e.g., OneOme, GeneSight), although their routine clinical use remains investigational [36]. Future studies validating genotype-dosing algorithms in prospective cohorts are needed before widespread adoption [37]. Molecular analyses and identification of ABC transporters polymorphisms and their functional interactions with both novel and established drugs serve as valuable indicators of the clinical efficacy of various anticancer agents in individual patients, with these interactions being influenced by individual genotypes.

10. Conclusions & recommendations

This review highlights the fact that ABC polymorphism can influence the fate of colorectal carcinoma at various levels like occurrence, prognosis of disease, treatment response, dose adjustment, development of resistance, and adverse effects of chemotherapy.

Polymorphisms in the ABC genes play a pivotal role in the overall picture of the disease.

Recent interest has emerged regarding the role of ABCB6 and ABCC10 in colorectal cancer (CRC) pharmacogenomics, although they remain less extensively studied than ABCB1 or ABCG2. ABCB6 encodes a mitochondrial outer membrane protein involved in porphyrin transport and heme biosynthesis. Emerging studies have shown that ABCB6 is overexpressed in several solid tumors, including CRC, and may contribute to chemoresistance through altered oxidative stress response and drug efflux mechanisms [38]. SNPs such as ABCB6 rs1051052 have been investigated in the context of drug-induced toxicity and may affect transporter function, though their precise prevalence in CRC-specific cohorts remains underexplored.

ABCC10 (also known as MRP7) is a member of the multidrug resistance protein family involved in the efflux of taxanes, vinca alkaloids, and platinum-based agents. It has been detected in colorectal tissue and cell lines, with studies suggesting its potential role in oxaliplatin disposition [30]. Notably, the ABCC10 rs2125739 polymorphism has been linked to improved overall survival in CRC patients treated with oxaliplatin-based regimens, highlighting its emerging relevance in CRC pharmacogenetics. While expression patterns may vary, the presence of functional SNPs in these transporters underscores their potential as predictive markers for treatment response and toxicity.

Funding Statement

This paper was not funded.

Article highlights

• Colorectal cancer treatment outcomes vary due to genetic polymorphisms in ABC transporters.

• Polymorphisms in ABCB1, ABCG2, ABCC2, and ABCA2 influence response to irinotecan, oxaliplatin, and capecitabine.

• SNPs such as ABCG2 rs2231142 and ABCB1 rs1045642 affect efflux capacity and toxicity.

• Ethnic differences in allele frequency explain variation in treatment outcomes.

• Genotype-guided therapy is a promising but underutilized component of personalized oncology.

Author contributions

• Conceptualization: SA

• Methodology: SA

• Literature search: ZSD, MS, ZB

• Analysis of Studies: SA, ZSD, MS, ZB, NM

• Validation: SA, NM

• Writing (original draft): ZSD

• Writing (review and editing): SA, NM

• Supervision: SA

• Project Administration: SA

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.