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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 782-786

DPYD*2A/*5A/*9A and UGT1A1*6/*28 polymorphisms in Chinese colorectal cancer patients


Molecular Testing Laboratory, Hanzhong 3201 Hospital, School of Medicine, Xi'An Jiaotong University' Shaanxi, China

Date of Web Publication25-Jul-2016

Correspondence Address:
Tao Liu
783, Tian han Road, Han tai District, Han zhong City, Shaanxi
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148685

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 > Abstract 


Aim of Study: Fluorouracil drugs and irinotecan are commonly used in the treatment of colorectal cancer (CRC), but some patients have severe toxic side effects in the conventional dose. DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 polymorphisms are related to the toxicity of fluorouracil drugs and irinotecan, respectively. Herein, we investigated the frequencies of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 genotypes in Chinese CRC patients.
Materials and Methods: For this study, 117 CRC patients' tumor tissues were examined through sequencing technology of the first generation to explore the distribution of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 genotypes.
Results: DPYD*2A G/G genotype accounted for 100%. DPYD*5A A/A, A/G, and G/G genotypes accounted for 48.2, 37.5, and 14.3%, respectively. DPYD*9A T/T and T/C genotypes accounted for 85.7 and 14.3%, respectively. UGT1A1 * 6 G/G, G/A, and A/A genotypes accounted for 74.6, 21.8, and 3.6%, respectively. UGT1A1 * 28 TA6/TA6, TA6/TA7, and TA7/TA7 genotypes accounted for 71.8, 27.3, and 0.9%, respectively. The genotypes of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 were not associated with patient's sex, age, and primary tumor sites. Our findings showed that: (i) almost 57.1% of Chinese CRC patients had at least one variant of DPYD*5A and DPYD*9A; (ii) nearly 37.3% of Chinese CRC patients had at least one variant of UGT1A1 * 6 and UGT1A1 * 28.
Conclusion: It suggests that it is necessary for Chinese CRC patients to detect the genotypes of DPYD*5A/*9A and UGT1A1 * 6/*28 before treating with fluorouracil drugs and irinotecan.

Keywords: Colorectal cancer, DPYD, gene polymorphism, toxicity, UGT1A1


How to cite this article:
Li GY, Duan JF, Li WJ, Liu T. DPYD*2A/*5A/*9A and UGT1A1*6/*28 polymorphisms in Chinese colorectal cancer patients. J Can Res Ther 2016;12:782-6

How to cite this URL:
Li GY, Duan JF, Li WJ, Liu T. DPYD*2A/*5A/*9A and UGT1A1*6/*28 polymorphisms in Chinese colorectal cancer patients. J Can Res Ther [serial online] 2016 [cited 2019 Dec 10];12:782-6. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/782/148685




 > Introduction Top


Colorectal cancer (CRC) is one of the most frequent malignancies in humans. Notable progress has been made in the treatment of CRC in recent years; especially the chemotherapy scheme based on the biomarkers can significantly improve the therapeutic effect of CRC. Fluorouracil drugs and irinotecanare commonly used chemotherapeuticsin clinical. Although advancements in medical treatment of CRC have led to a reduced risk of recurrent disease and an improved outcome of patients; all CRC patients will benefit from chemotherapeutic treatments. One reason for this outcome might be that the initial dose given is too high at the individual level, resulting in toxic side effects.[1] The development of pharmacogenomics and gene detection technology laid the foundation to reveal the cause of these discrepancies, also provide the reference for the clinical treatment.[2] Accurate understanding of the patients' genetic conditions can help them achieve good curative efficacy.[3],[4],[5]

Fluorouracil drugs were introduced into clinical use more than 50 years ago and has become the most commonly used anticancer drug for treatment of CRC.[6] Although fluoropyrimidine drugs are generally well-tolerated, approximately 10% of the patients suffer from severe fluoropyrimidine-induced toxicity.[7] The cytotoxicity of fluorouracil (5-FU) is thought to be secondary to: (1) Inhibition of thymidylatesynthase (TS), principally via the actions of its metabolite, fluorodeoxyuridinemonophosphate (FdUMP); (2) synthesis of defective ribonucleic acid (RNA) as a result of incorporation of a second metabolite, fluorouridinetriphosphate (FUTP), into RNA.[8] The most common fluorouracil toxicities include neutropenia, mucositis, diarrhea, and hand–foot syndrome.[9] The dihydropyrimidinedehydrogenase gene (DPYD) is located on chromosome 1p22 and consists of 23 exons.[10] Dihydropyrimidinedehydrogenase (DPYD) is the initial and rate-limiting enzyme in the catabolism of pyrimidines, as it inactivates up to 85% of 5-FU to 5,6-dihydro-5-fluorouracil.[11] The decrease inDPYD enzymatic activity leads to the blocking of fluorouracil clearance in vivo, theprolonged half-life and the enhanced cytotoxicity.[12]DPYD polymorphism is closely related to its enzyme activity. The clinically most relevant polymorphism in DPYD is DPYD*2A (IVS14þ1G > A), a single nucleotide substitution at the invariant splice donor site of intron 14 that leads to skipping of exon 14 during pre-messenger RNA (mRNA) splicing.[7] As a consequence, a truncated protein is formed with absent DPYD activity.[13],[14]

Indeed, DPYD enzyme activity in heterozygous individuals for IVS14þ1G > A is on average reduced by approximately 50% compared with the population average.[15],[16],[17]DPYD*5A (1627A > G, I543V) and DPYD*9A mutants are common in Chinese population. All the mutants can reduce the activity of DPYD. Fluorouracil toxicity will increase in the patients that contain DPYD mutants. Fluorouracil toxicity will increase in the patients that contain DPYD mutants, so they should avoid or reduce the dose of fluorouracil.

Irinotecan is a widely used anticancer drug that has been approved for the treatment of advanced CRC.[18] The mechanism of action of irinotecan is associated with topoisomerase I inhibition by the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which results in cytotoxic effects on rapidly dividing cells.[19] The most common side effects are bone marrow toxicity, leading to abnormally low blood counts, and ileocolitis, which often results in severe diarrhea.[20] SN-38 is 100- to 1,000-fold more potent than irinotecan as a to poisomerase I poison. SN-38 is eliminated predominantly by glucuronidation to SN-38 glucuronide (SN-38G). This glucuronidation reaction is mediated primarily by UDP-glucuronosyltransferase 1 family polypeptide A1, which is encoded by the UGT1A1 gene.[21] Studies reported that the enzyme activity of UGT1A1 was closely associated with the genetic polymorphisms of UGT1A1, especially UGT1A1 * 28and UGT1A1 * 6.[22]UGT1A1 * 28 polymorphism was generated by the change of TA repeats in the TATA box ofUGT1A1 promoter, resulting in three genotypes: TA6/TA6 (wild type), TA6/TA7 (heterozygosity), and TA7/TA7 (homozygosity).[23]UGT1A1 * 28 mutant reduces70% transcriptional activity compared with wild-type UGT1A1.[24]UGT1A1 * 6 results by the substitution of glycine for arginine at position 71 (G71R) of the UGT1A1 protein. Studies have reported that polymorphism of UGT1A1 * 6 was associated with irinotecan-induced diarrhea and neutropenia in Asians, especially neutropenia.[25]

The objective of the present study was to investigate the genotypic and allelic frequencies of DPYD*2A/5A/9A and UGT1A1 * 6/28 polymorphisms in Chinese CRC patients. The research can provide the basis for clinical use of fluorouracil drugs and irinotecan, avoiding some CRC patients who experience serious side effects in the conventional medication dose.


 > Materials and Methods Top


Subjects

A total of117 which histologically confirmed CRC were enrolled into this study. All of them were operated in our hospital between January 2012 and June 2014. Paraffin-embedded tissue samples of the patients were considered eligible. Patients did not receive previous chemotherapy, radiotherapy, or have other malignant tumor history in5 years before this study.

Deoxyribonucleic acid extraction and polymorphism detection

Tumor tissues were scraped from paraffin-embedded tissue sections. Total Deoxyribonucleic acid (DNA) was extracted with CWBio (CWBio, Shanghai, China) and dissolved in water, according to the manufacturer's instructions. The primers for DNA analysis have been presented in [Table 1]. Reverse transcription polymerase chain reaction (RT-PCR) in reaction volume of 15 µL was performed with the protocol consisting of an initial denaturation at 94°C for 4 min, followed by 26 cycles of 94°C for 30 s, 54°C for 30 s, 72°C for 30 s, and a final extension at 72°C for 10 min. PCR products were confirmed by 1.5% agarose gel electrophoresis and sequenced byIn vitro gen 3730XL genetic analyzer. The sequencing results were analyzed with Chromas software under the condition of signal/noise >98%. Each sample was sequenced at least twice. Genotypes were described as G/G for DPYD*2A; A/A, A/G, G/G for DPYD*5A; T/T, T/C for DPYD*9A; GG, GA, AA for UGT1A1 * 6; and TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1 * 28 [Figure 1] and [Figure 2].
Table 1: Primes for gene analysis

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Figure 1: Sequencing results of different DPYD*2A/5A/9A genotypes

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Figure 2: Sequencing results of different UGT1A1*6/*28 genotypes

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Statistical analysis

For statistical analysis, R was used. Fisher's test was used to determine the difference of genotype frequencies among DPYD*2A/*5A/*9A and UGT1A1 * 6/*28. All statistical analyses were two-sided test, and P < 0.05 was considered as significant difference.


 > Results Top


Patient characteristics

The patient characteristics were summarized in [Table 2]. Median age of the patients was 61 years (range: 22-88 years). There were 69 males (59%), 48 females (41%), 52 cases of rectal cancer, and 65 cases of colon cancer. Patients had not received previous chemotherapy, radiotherapy, or had other malignant tumor history during 5 years before this study.
Table 2: Patient characteristic

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Genotyping of DPYD*2A/5A/9A in CRC cancer

A total of 112CRC patients (48 rectal cancer and 64colon cancer) were analyzed in this study with 64 males and 48 females, and median age of 61 years (range 22–88 years). As shown in [Table 3], the frequencies of wild type genotype (A/A), heterozygous genotype (A/G), homozygous genotype (G/G) for DPYD*5A and wild type genotype (T/T), heterozygous genotype (T/C), and homozygous genotype (C/C) for DPYD*9A were 48.2% (n = 54), 37.5% (n = 42), 14.3% (n = 16) and 85.7% (n = 96), 14.3% (n = 16), and 0 (n = 0), respectively. It was interesting to observe that only DPYD*2A had G/G genotype. The mutation rates of DPYD*2A/*9A/*5A had significant differences (0 < 14.3%<51.8%, P < 0.05). We divided patients into three groupsaccording to the numbers of mutational alleles (DPYD*5A/*9A): Wild type (patients with genotype: A/A and T/T, n = 48, 42.9%), single allele variants (patients with genotype: A/A and T/C; or A/G and T/T; n = 38, 33.9%), and two allele variants (patients with genotypes: A/G and T/C; or G/G and T/T; n = 26, 23.2%). No significant differences were seen between DPYD*2A/*5A/*9A variants and patients' sex, age, and primary tumor sites.
Table 3: Genotyping of DPYD in CRC patients

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Genotyping of UGT1A1 * 6/*28 in CRC cancer

A total of 110 CRC patients (52 rectal cancer and 58 colon cancer) were analyzed in this study with 69 males, 41 females, and the median age of 61 years (range 22–88 years). As shown in [Table 4], the frequencies of wild type genotype (G/G), heterozygous genotype (G/A), homozygous genotype (A/A) for UGT1A1 * 6 and wild type genotype (TA6/TA6), heterozygous genotype (TA6/TA7), homozygous genotype (TA7/TA7) for UGT1A1 * 28 were 74.6% (n = 82), 21.8% (n = 24), 3.6% (n = 4) and 71.8% (n = 79), 27.3% (n = 30), and 0.9% (n = 1), respectively. Seven patients (6.4%) carried double heterozygosity (G/A concurrent with TA6/TA7), and the A/A and TA7/7A7genotype were exclusive in this study. We further divided patients into four groups according to numbers of mutational alleles: Wild type (patients with genotype: G/G and TA6/TA6, n = 59, 53.6%), single allele variants (patients with genotypes: G/A and TA6/TA6; or G/G and TA6/TA7; n = 39, 35.5%), and two allele variants (patients with genotypes: A/A and TA6/TA6; or G/A and TA6/TA7; or G/G and TA7/TA7; n = 11, 10%), and three allele variants (patients with genotypes: A/A and TA6/TA7, n = 1, 0.9%). No significant differences were seen between UGT1A1 * 6/*28 variants and patients' sex, age, and primary tumor sites. There was no significant difference between UGT1A1 * 6 and UGT1A1 * 28 mutation rates.
Table 4: Genotyping of UGT1A1 in CRC patients

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 > Discussion Top


Fluorouracil and irinotecan are commonly used chemotherapeutics, clinically, to treat CRC. Although they have made good curative effects in clinic, but there are significant differences among different patients.[7],[24] It relates to individual's tolerance to drug toxicity mechanism. Many studies had reported that DPYD and UGT1A1 polymorphisms were associated with the toxicity of fluorouracil and irinotecan.[1],[7] More than 50 polymorphisms in DPYD have been identified to date.[26],[27]DPYD*2A/*5A/*9Awere considered to be the clinically relevant polymorphisms in DPYD.[12],[28] Although more than 50 genetic lesions in the UGT1A1 gene have been described, the UGT1A1 * 6/*28 alleles play a crucial role in the development of toxicity after irinotecan chemotherapy.[24]

DPYD*2A was considered to be the clinically most relevant polymorphism in DPYD.[7] But in our study no DPYD*2A variant was detected. Hsiao's research of Taiwan population found the same phenomenon.[29] In contrast, the prevalence of DPYD*5A/*9A alleles' variants were much higher in Chinese patients compared to DPYD*2A. There were significant differences among the mutation rates of DPYD*2A/*5A/*9A. The frequency of DPYD*5A/*9A variants were 51.8 and 14.3%, respectively. Heterozygous genotypes were the main mutation types of DPYD*5A/*9A and no DPYD*9A homozygous variant was found. Only 10 (8.9%) patients carried DPYD*5A and DPYD*9A mutations. But64 (57.1%) patients carried at least one mutation. It means that almost 57.1% CRC patients' DPYD enzymatic activity reduced and it will lead to increase in fluorouracil toxicity.

The role of UGT1A1 * 28 polymorphism in the development of irinotecan-induced diarrhea has been documented in many studies from western countries.[30] Thus, in 2005, the US Food and Drug Administration (FDA) claimed that UGT1A1 * 28 testing should be included in the label of irinotecan as a risk factor for severe toxicity. According to our results the mutation rate ofUGT1A1 * 28 was 28.2%, much lower than Lyer'sresearch result,[31] but a little higher than Gao's research result.[23] Studies suggested that the UGT1A1 * 6 allele was an important factor to predict severe neutropenia.[32] Gao's research result showed that the prevalence of UGT1A1 * 6 allele was much higher in Chinese patients compared to Whites.[23] But our results showed that the mutation rate of UGT1A1 * 6 was 25.5%. The reason for this phenomenon may be due to the difference of the selected population. There was no significant difference between the mutation rates of UGT1A1 * 6 and UGT1A1 * 28. Heterozygous genotypes were the main mutation types ofUGT1A1 * 6/*28. Only four (3.6%) patients carried A/A genotype, one (0.9%) carried TA7/TA7 genotype, and 11 (10%) carried UGT1A1 * 6 and UGT1A1 * 28 mutations.

Patients should receive different treatments according to their genotypes. The dose of fluorouracil or irinotecan should be reduced and monitored more closely in patients with DPYD*2A/*5A/*9A or UGT1A1 * 6/*28 mutations. Once serious side effects appear, clinician should consider other drugs. Although, genotype detection would consume sometime; but, it is very necessary.

In summary, in Chinese CRC patients more than half have DPYD*5A or DPYD*9A mutations and more than quarter have UGT1A1 * 6 or UGT1A1 * 28 mutations. So Chinese CRC patients should be tested for genotypes of DPYD*5 A/*9A and UGT1A1 * 6/*28 before they receive fluorouracil and irinotecan chemotherapy.

 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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