Association of glutathione-S-transferase M1,P1, and T1 gene polymorphisms with treatment response in childhood acute lymphocytic leukemia

@#<p style="text-align: justify;">There is still a strong need for new treatment strategies that will maintain remission and prolong survival in patients with acute lymphoblastic leukemia (ALL). The glutathione-S-transferase (GST) enzymes, which are coded by highly polymorphic genes, have been associated with the risk of developing cancer and were found to regulate effect of cancer treatment drugs.<br /><strong>OBJECTIVES:</strong> The present study determines the association of GSTM1, GSTP1 and GSTT1 polymorphisms and treatment response in terms of occurrence of adverse events and relapse in ALL in Filipino children.<br /><strong>METHODS:</strong> This is a follow up study on the 2007 investigation done by Alcausin et al. which determined the association of the GST P1, M1, and T1 polymorphisms and occurrence of ALL. Four-year follow-up data were available for 46 out of the 50 patients from January 2007 to May 2011. Odds ratios (OR) as measures of association of GST M1, P1 and T1 gene polymorphisms with treatment outcomes were estimated at 95% confidence interval.<br /><strong>RESULTS:</strong> Results show a trend towards predisposition to elevation of liver enzymes in patients with GSTT1 and GSTP1 mutant genotypes showing an OR (95% Cl) of 2.0 (0.62-6.49). The presence of GSTM1 null genotype showed a trend towards protection from occurrence of relapse basing on both crude and adjusted ORs, 0.58 (0.16-2.07) and 0.23 (0.05-1.20), respectively. However, these results are not statistically significant.<br /><strong>CONCLUSION: </strong>The GSTP1 heterozygous genotype conferred increased predisposition to elevation of liver enzymes while the GSTT1 null genotype was shown to be a possible risk factor towards the occurrence of both infection and elevation of liver enzymes during chemotherapy. Furthermore, the GSTM1 null genotype appears to be protective from occurrence of relapse. It is recommended to do similar large-scale studies in the future to obtain more conclusive results.</p>

Genetic polymorphisms in CYP1A1, GSTM1, GSTP1, GSTT1, NAT1 and NAT2 and oral cavity cancer risk among Filipinos

Polymorphisms in metabolic genes have been shown to modulate susceptibility to oral cavity cancer. Cases (n=176) and controls (n=317) from the Filipino population were genotyped for selected polymorphisms in CYP1A1, GSTM1, GSTP1, GSTT1, NAT1 and NAT2. Medical and diet histories, occupational exposure and demographic data were also collected for all subjects. The CYP1A1m1/m1 genotype is protective against oral cancer, while being homozygous for the GSTP1 c.313G genotype and heterozygous for the NAT1*10 homozygotes and non-homozygotes for the CYP1A1 m1 allele. The risk from heterozygosity for the NAT1*10 allele was limited to subjects who were not homozygous for the GSTP1 c.313G genotype remained a significant oral cancer risk modifier, together with environmental variables, the homozygous GSTP1 c.313G genotype remained a significant oral cancer risk modifier, together with environmental risk factors, such as smoking, passive smoking, inverted smoking and tobacco chewing, and environmental protective factors, i.e. moderate consumption of fish sauce (patis) and shrimp paste (bagoong). The GSTP1 c.313G polymorphism increases susceptibility for oral cavity cancer in the Filipino population.

Birth defects ascertainment in the Philippines.

In the Philippines, congenital anomalies rank among the top 20 causes of death across the life span and are already the third leading cause of death in the infancy period (Philippine Department of Health, 1996). Despite the magnitude of the problem, no formal systematic registration of birth defects has been done in the country up until 1999. Various attempts have been made by different study groups to gather data but there was never a formal effort to consolidate the information and establish a centralized registry. Data from various modes of ascertainment are hereby presented: 1) Philippine Birth Defects Registry Project, 2) Hospital In-Patient and Out-Patient Registries, 3) Prenatal Inventory and Neonatal Outcome Study Group, 4) Hospital Pathology Reports, and 5) Community Outreach Programs. Birth Defects Registry Project had the largest reporting of the different methods presented here. The most common birth defects were multiple congenital anomalies, congenital malformations of the tongue, mouth, and pharynx (ankyloglossia), cleft palate with cleft lip, Down Syndrome, congenital deformities of the feet (talipes equinovarus), anencephaly, other congenital malformations of the face and neck, congenital malformations of the musculoskeletal system (diaphragmatic hernia, gastroschisis), hypospadias, congenital hydrocephalus, polydactyly, syndactyly, and cleft lip.

Cost-benefit analysis of newborn screening for galactosemia in the Philippines.

To determine the incidence of galactosemia (GAL) in the Philippines and to determine whether newborn screening for GAL is cost-beneficial from a societal perspective, cost-benefit analysis was performed. Newborn screening for GAL was done after the 24th hour of life using the Beutler test. Patients screened positive were recalled for confirmatory testing. Using incidence rates obtained from the different participating hospitals of the Philippine Newborn Screening Program (PNSP), the costs for the detection and treatment of GAL were compared to the expected benefits by preventing mental retardation, cataracts and other physical disabilities caused by the disorder that would lead to a loss of productivity for the individual. Sensitivity analyses for incidence and discount rates were also included. Of the 157,186 newborns screened by the PNSP since its inception in 1996, 8 screened positive results. Confirmatory testing of these patients showed that 2 had galactosemia. The incidence of galactosemia in this population therefore, is 1 in 106,006 (95% CI= 1:44,218 - 1:266,796). Projecting the figures to the actual birth rate (1.5M newborns/year), the total costs of the screening program amounted to $1.1M, while the total benefits amounted only to $0.2M, yielding net cost of $0.9M. A cost-benefit analysis of the screening program for galactosemia using the incidence 1 in 106,006 demonstrated that the costs of the program outweigh the benefits. The true incidence of galactosemia in the Philippine population may yield an incidence rate that will result in greater net benefits for the program.

Hyperphenylalaninemia in the Philippines.

To present patients with hyperphenylalaninemia (HPA) diagnosed by routine newborn screening and to discuss the principles in managing hyperphenylalaninemia, retrospective clinical chart review was conducted. Newborn screening for phenylketonuria (PKU) was performed using the Guthrie Test or Bacterial Inhibition Assay, utilizing dried blood spots on special filter cards. Positive screens were confirmed through plasma amino acid determination, urinary pterins for tetrahydrobiopterin deficiency, enzyme analysis. Once confirmed, the patients were kept on low-phenylalanine diet and regularly monitored for blood phenylalanine levels and developmental profile. A total of 189,720 newborns were screened from 1996--2001. Seventy five screened positive for PKU; 41 returned for retest; 3 were confirmed positive for HPA. This paper presents the first two cases of HPA detected by the Philippine Newborn Screening Program. The management of each case upon diagnosis is discussed. The significance of early detection and treatment of HPA is emphasized.

Newborn screening for congenital hypothyroidism in early discharged infants.

A study of newborn thyroid stimulating hormone (TSH) levels was undertaken to determine whether a quantitative relationship exists between TSH values obtained between the 12th to 24th hours of life and the 48th to 72nd hours of life. The study was designed to: (a) measure TSH levels in full term newborns between the 12th - 24th hours of life, (b) measure TSH levels in the same set of newborns at 48 - 72 hours of life, (c) correlate TSH values obtained during the two time periods of specimen collection, (d) determine whether TSH results at 12 to 24 hours are predictive of TSH levels at 8 to 72 hours, and (e) determine the effects of other factors on TSH 48-72. One thousand three hundred seventy full term normal infants delivered at the Philippine General Hospital and at the Rizal Medical Center from August 1999 to March 2001 participated in the study. Eighty-three percent were from Metro Manila and the rest from the provinces. Although there was a significant association between TSH12-24 and TSH48-72, the magnitude of association could not account for all of the variance in the TSH48-72 values. By itself, TSH12-24 cannot clinically predict 48-72 hour TSH levels. Multiple regression analysis showed that sex and mode of delivery by cesarean section were significant factors affecting TSH levels at 48-72 hours.

Beyond screening: challenges in measuring outcomes.

There are several important messages for pediatricians concerned with what happens to patients after identification through newborn screening. Particularly important in many of the disorders are the developmental aspects of outcome. There are certain basic assumptions that are essential in improving developmental outcome as a result of newborn screening: 1) newborn screening leads to early case identification; 2) early diagnosis and intervention generally enhance developmental outcome; 3) sustained compliance is crucial for better developmental outcome; 4) increased awareness of other factors improves developmental outcome; 5) periodic developmental monitoring ensures quality follow-up. Even though the Philippine Newborn Screening Program is young, there are already experiences in these areas to draw from. Likewise, there are strategies that can be employed to overcome the challenges in a developing country, which can lead to better follow-up, characterized by desirable critical features of availability, accessibility, affordability, accuracy and adequacy.