The influence of glutathion S-transferase P-1 polymorphism A313G rs1695 on the susceptibility to cyclophosphamide hematologic toxicity in Indonesian patients

Latar belakang: Kemoterapi sering menimbulkan efek samping berupa toksisitas hematologi. Derajat toksisitas yang timbul sering dikaitkan dengan polimorfisme genetik. Penelitian ini bertujuan mengetahui apakah polimorfisme genetik GSTP1 A313G yang berperan pada detoksifikasi siklofosfamid dapat memprediksi insidensi dan derajat toksisitas hematologi siklofosfamid. Metode: 91 perempuan Indonesia yang telah didiagnosis kanker payudara di RSUP Haji Adam Malik, Medan dan diterapi dengan regimen siklofosfamid, doxorubicin/epirubicin, dan 5-FU diikutsertakan pada penelitian kohort retrospektif ini. DNA diekstraksi dari leukosit perifer pasien dan dilanjutkan dengan pemeriksaan genotipe GSTP1 A313G dengan metode polymerase chain reaction-restriction length fragment polymorphism (PCR-RFLP). Distribusi frekuensi genotipe dan alel ditentukan dengan Hardy-Weinberg Equilibrium. Data derajat toksisitas hematologi (leukopenia dan neutropenia pasca-kemoterapi siklus 1 dan 3) dikumpulkan dari rekam medis pasien dan dianalisis dengan uji Kai kuadrat. Antar kelompok genotipe yang berbeda. Hasil: Didapatkan proporsi GSTP1 A313A (wild type) 60,4%, GSTP1 A313G (heterozigot mutan) 29,7%, dan GSTP1 G313G (homozigot mutan) 9,9%. Tidak ada penyimpangan frekuensi genotipe dan alel yang signifikan terhadap Hardy-Weinberg Equilibrium. Ditemukan pasien dengan alel G (A/G&G/G) cenderung mengalami leukopenia dengan derajat yang lebih berat dibandingkan dengan pasien GSTP1 wild type alel (A/A) pasca-kemoterapi siklus ke-3 (p<0,05). Kesimpulan: Polimorfisme GSTP1 exon 5 A313G memiliki hubungan dengan derajat toksisitas hematologi pada pasien kanker payudara yang mendapat kemoterapi siklofosfamid. Background: Chemotherapy often causes side effects such as hematologic toxicity. The degree of toxicity is often associated with genetic polymorphism. This study aims to determine the influence of GSTP1 A313G polymorphism, an enzyme responsible for detoxifying cyclophosphamid, on incidence and severity of cyclophosphamid hematologic toxicity. Methods: 91 Indonesian females diagnosed with breast cancer at Haji Adam Malik Central General Hospital, Medan, receiving cyclophosphamide, doxorubicin/epirubicin and 5-FU were included in this retrospective cohort study. DNA was extracted from peripheral leukocytes and GSTP1 A313G genotyping was analyzed using polymerase chain reaction-restriction length fragment polymorphism (PCRRFLP). Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium. The degrees of hematologic toxicity (leucopenia and neutropenia data after chemotherapy cycles 1 and 3) were collected from the patient medical records. The data were analyzed using chisquare test. Results: 60.4% of the patients had the wildtype (A/A), while 29.7% were heterozygous (A/G), and 9.9% were homozygous mutant (G/G). There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. The G allele (A/G & G/G) contributes to more severe degree of leukopenia compared to patients with wild type allele (A/A) (p<0.05) after the 3rd chemotherapy cycles. Conclusion: There was association between GSTP1 polymorphism with the degree of hematologic toxicity in breast cancer patients receiving cyclophosphamide chemotherapy regimen.