Introduction and aimsTamoxifen is an adjuvant drug effective in treating hormone receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka.MethodsA retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay.ResultsSNP/allele frequencies detected: 1846G>A (confirmatory of *4 null allele)=8.3%; 2549delA (confirmatory of *3 null allele)=50%; 100C>T (suggestive of *10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, −1584C and 2850C>T (strongly suggestive of *41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with −1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested.ConclusionsCYP2D6 SNP combination 2988G>A, −1584C and 2850C>T, strongly suggestive of *41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients.
Background: Hepatocellular carcinoma (HCC) is becoming a challenging global health concern with Asian and African countries carrying the highest burden of it. The rising prevalence of non-alcoholic steatohepatitis (NASH) associated HCC is linked with unhealthy dietary patterns and sedentary life styles. In addition, genetic predisposition may play a critical role in developing NASH-related HCC. Previous studies have identified that variants in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are significantly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. But there are no published reports on their impact on Sri Lankan NASH-HCC patients.
Methods: We conducted an exploratory study to evaluate the prevalence of five single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, PNPLA3rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC samples that were collected at a clinical setting and analyzed using statistical modelling to explore the impact of each SNP with tumor prognostic factors.
Results: We observed high frequencies in four out of five polymorphisms, namely PNPLA3 rs738409 (0.79, 95%CI 0.650-0.895), PNPLA3 rs2281135 (0.77, 95%CI 0.627-0.880), PNPLA3 rs2294918 (0.9, 95%CI 0.773-0.965) and MBOAT7rs641738 (0.85, 95%CI 0.722-0.939) among Sri Lankan NASH-HCC patients. Our analyses further demonstrated significant associations of PNPLA3variants with a total tumor diameter of NASH-HCC patients while PNPLA3 rs2294918 and MBOAT7 rs641738 had significant associations with single-nodular HCC. Of the five SNPs, we observed a strong correlation between PNPLA3 rs738409 and PNPLA3 rs2294918 through pairwise linkage disequilibrium (LD) analysis.
Conclusion: Observed high frequencies of risk alleles among genotyped SNPs warrants the possibility of genetic predisposition as a risk factor for NASH-related HCC in the Sri Lankan setting.
Introduction Growth hormone releasing hormone receptor (GHRH-R) codon 72 mutation is recognised as a common genetic cause of growth hormone deficiency (GHD) in the Indian subcontinent resulting in a characteristic lean phenotype. Genetic studies have not been previously carried out in Sri Lankans with GHD.Methods Patients with GHD presenting to a tertiary care referral centre were studied for GHRH-R codon 72 mutation by PCR amplification and sequencing. The phenotype of the cohort was described as the BMI SDS (Body mass index standard deviation score) based on the anthropometric data at the time of diagnosis.Results Among 91 patients from 88 families studied, eight (6 boys) carried the codon 72 mutation. The presence of this mutation was low among the Sinhalese ethnicity (3 out of 68) than among Tamil and Moor ethnicities. BMI SDS of <-2 was seen in 71% of mutation positive and 45.8% of mutation negative patients.
ConclusionsPrevalence of GHRH-R codon 72 mutation in this group of GH deficient patients was 8.8%. The lean phenotype observed in 71% of the mutation positive patients was not a significant association when compared to a similar phenotype in 45.8% of the mutation negative patients.
Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency
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