Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

Abstract

Background Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment. Methods Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drug-based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. Results The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 38.4%, 24%, and 32.7%, respectively. DPYD*2A variant was not found. A total of 23 patients (22.1%) suffered severe vomiting and 19 patients (18.3%) suffered severe anemia. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe vomiting and skin ulceration (p = 0.042 and p = 0.018, respectively). Patients with GSTP1 c. 313A>G mutant type contributed to a higher risk for grade severe toxicity compared with wild genotype (p = 0.027). Nevertheless, no significant difference was found between patients with DPYD*2A, *5A, and *9A for chemotherapeutic toxicity. Conclusions The results demonstrated that GSTP1 polymorphisms were useful predictors of severe events. Screening of single-nucleotide polymorphisms of GSTP1 in colorectal cancer patients before chemotherapy may help to realize personalized therapy.

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

“…According to the FDA, the toxicity caused by these drugs is distinguished by the development of mucositis, stomatitis or esophagopharyngitis, diarrhea (grade 3 or 4), palmar-plantar erythrodysesthesia (hand-foot syndrome), myelosuppression, hyperammonemic encephalopathy, and systemic toxicity. Toxicity grade 3 occurs in 25–30% of patients treated with this group of drugs [ 9 , 10 ], and is characterized by the development of neutropenia and leukopenia, vomiting, and skin ulceration [ 11 , 12 ]. Regarding systemic toxicity, in 1–18% of patients, one can observe the development of a spectrum of cardiac problems ranging from coronary ischemia, systolic left ventricular dysfunction, arrhythmias, and sudden death [ 13 ].…”

GSTP1 c.313A > G mutation is an independent risk factor for neutropenia hematotoxicity induced by anthracycline-/paclitaxel-based chemotherapy in breast cancer patients

“…For example, Deng et al found that colorectal cancer patients with GSTP1 c.313A > G mutation who received treatment with fluoropyrimidines and oxaliplatin had an increased risk of severe vomiting (grade III/IV), but there was no relationship between the polymorphism and neutropenia. And it showed that GSTP1 c.313A > G mutation may be an independent risk factor for severe vomiting induced by chemotherapeutic drugs [ 43 ].…”

Gene polymorphism and prediction of toxicity to platinum‐based chemotherapy in patients with gynecologic cancer

“…11 A growing number of genes and motifs have been reported to be associated with PPCT toxic responses or genetic alterations, including the glutathione S transferase Pi 1 (GSTP1) gene rs1695, methylenetetrahydrofolate reductase (MTHFR) gene rs1801133, xeroderma pigmentosum complementation group C (XPC) gene rs2228001, tumor protein p53 (TP53) gene rs1042522, and excision repair cross-complementation group 1 (ERCC1) gene rs3212986, which provides a broader perspective to facilitate the development of precision medicine. [12][13][14][15][16] In the present study, we recruited 244 patients recently diagnosed with cervical, ovarian, uterine, or fallopian tube cancer. SNPs at rs1695, rs1801133, rs2228001, rs1042522, and rs3212986, were characterized by performing multichannel fluorescence real-time quantitative polymerase chain reaction (PCR) on specimens of peripheral blood.…”

“…The Human Genome Project has identified millions of SNPs; the corresponding relationships with responsiveness to drugs (including antitumor drugs) has received increasing attention 11 . A growing number of genes and motifs have been reported to be associated with PPCT toxic responses or genetic alterations, including the glutathione S transferase Pi 1 ( GSTP1 ) gene rs1695, methylenetetrahydrofolate reductase ( MTHFR ) gene rs1801133, xeroderma pigmentosum complementation group C ( XPC ) gene rs2228001, tumor protein p53 ( TP53 ) gene rs1042522, and excision repair cross‐complementation group 1 ( ERCC1 ) gene rs3212986, which provides a broader perspective to facilitate the development of precision medicine 12–16 …”