Yip Cheng Har

Genetic polymorphisms of paraoxonase 1 (PON1) gene: association between L55M or Q192R with breast cancer risk and clinico-pathological parameters

The aim of the present study was to evaluate the association between the paraoxonase 1 (PON1) L55M and Q192R polymorphisms and breast cancer risk as well as clinico-pathological characteristics of the patients. Genotyping of these polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The genotype (P = 0.023) and allele (P = 0.008) frequencies of L55M polymorphism were significantly different between the breast cancer cases and normal individuals. However, the distribution of genotype (P = 0.333) and allele (P = 0.163) frequencies of Q192R polymorphism showed lack of statistical significance. Women who were MM homozygotes (OR = 2.229; 95% CI, 1.219–4.075) and carriers of M allele genotype (OR = 1.429; 95% CI, 1.035–1.974) or M allele (OR = 1.397; 95% CI, 1.093–1.785) were associated with increased risk of breast cancer. However, women who were heterozygous (OR = 0.793; 95% CI, 0.567–1.110) or homozygous (OR = 0.746; 95% CI, 0.407–1.370) for R allele or carriers of R allele (OR = 0.838; 95%, 0.654–1.074) were not associated with breast cancer risk. The M allele genotype was significantly associated with estrogen receptor negativity (P = 0.046) and nodal involvement (P = 0.004) but R allele genotype was not associated with any of the clinico-pathological characteristics. In conclusion, our findings suggest that the polymorphic variant of L55M polymorphism could be a useful genetic marker for tumor prognosis and to identify women who might be at greater risk of developing breast cancer in a hospital-based Malaysian population.

Polymorphism of FGFR4 Gly388Arg does not confer an increased risk to breast cancer development.

The genotype analysis of the Gly and Arg allele at codon 388 of fibroblast growth factor receptor-4 (FGFR4) gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The aim of the present study was to evaluate the association between the FGFR4 Gly388Arg polymorphism and breast cancer risk as well as clinicopathological parameters of the patients. The Gly/Gly, Gly/Arg, Arg/Arg, and Arg allele genotypes were detected in 46.3%, 44.4%, 9.3%, and 53.7% of breast cancer cases, respectively. The distribution of genotype (p = 0.204) and allele (p = 0.086) frequencies of FGFR4 polymorphism were not significantly different between the breast cancer cases and normal individuals. Women who were Arg/ Arg homozygotes (OR = 1.714, 95% CI 0.896-3.278), Gly/Arg heterozygotes (OR = 1.205, 95% CI 0.863-1.683), carriers of Arg allele genotype (OR = 1.269, 95% CI 0.921-1.750), or Arg allele (OR = 1.246, 95% CI 0.970-1.602) were not associated with breast cancer risk. The Arg allele genotype was significantly associated with lymph node metastases (p = 0.001) but not with other clinicopathological parameters. Our findings suggest that the polymorphic variant at codon 388 of FGFR4 gene does not confer increased risk to breast cancer development but it may be a potential genetic marker for tumor prognosis.

Analysis of peptidyl-propyl-cis/trans isomerase 1 (PIN1) gene −842(G > C) and −667(T > C) polymorphic variants in relation to breast cancer risk and clinico-pathological parameters

Abstract Background. The purpose of this study was to investigate the association between the peptidyl-propyl-cis/trans isomerase 1 (PIN1) −842(G > C) and −667(T > C) polymorphic variants and breast cancer risk among Malaysian ethnic groups namely the Malays, Chinese and Indians, as well as clinico-pathological characteristics of the patients. Patients and Methods. The polymerase chain reaction-restriction fragment length polymorphism was used to genotype 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. Results. The distribution of −842(G > C) and −667(T > C) genotypes and alleles frequencies between breast cancer cases and normal individuals showed lack of statistical significance among the Malays (p > 0.05), Chinese (p > 0.05) and Indians (p > 0.05), respectively. Multivariate logistic regression analysis showed that the Malay, Chinese and Indian women who were −842CC homozygotes (p = 0.198, 0.089, 0.620), −842GC heterozygotes (p = 0.492, 0.176, 0.377) and −842C allele carriers (P = 0.226, 0.059, 0.669), respectively, were not associated with breast cancer risk. Furthermore Malay, Chinese and Indian women who were heterozygous (p = 0.777, 0.319, 0.710) and homozygous (p = 0.864, 0.986, 0.954) for −667C allele or carriers of −667C allele (p = 0.977, 0.915, 0.880), respectively, were not associated with an increased risk of breast cancer. None of the −842C and −667C allele genotypes were significantly associated with the clinico-pathological characteristics. Conclusion. Our findings suggest that the polymorphic variants of −842(G > C) and −667(T > C) genes may not appear to have an influence on breast cancer risk among Malaysian Malay, Chinese and Indian women.

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array.

Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (≥ 30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (≥ 20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1‑p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy-neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (≥ 30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12‑q24.13 and 14q23.1. These findings offer compre-hensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the develop-ment of prospective therapeutics.

Genetic polymorphisms of TP53-binding protein 1 (TP53BP1) gene and association with breast cancer risk.

Naidu R, Har YC, Taib NAM. Genetic polymorphisms of TP53‐binding protein 1 (TP53BP1) gene and association with breast cancer risk. APMIS 2011; 119: 460–67.

Polymorphic Variant Ser128Arg of E-Selectin is Associated with Breast Cancer Risk and High Grade Tumors

Background: The present study aimed to evaluate the association between the E-Selectin Ser128Arg polymorphism and breast cancer risk and clinicopathological characteristics of the patients. Materials and Methods: The genotypes of 387 breast cancer patients and 252 healthy women who had no history of any malignancy were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a hospital-based Malaysian population. Results: The frequency of the Arg allele was significantly (p = 0.030) higher in breast cancer patients than in healthy individuals. Women who were Ser/Arg heterozygotes (adjusted odds ratio (ORadj) = 1.607; 95% confidence interval (CI) = 1.008–2.564), and carriers of the Arg allele genotype (ORadj = 1.587; 95% CI = 1.037–2.430) or Arg allele (ORadj = 1.509; 95% CI = 1.040–2.189) showed a significantly increased risk of breast cancer. Patients who were carriers of the Arg allele genotype showed a significant association with poorly differentiated tumors (p = 0.002). Conclusion: The Ser128Arg polymorphism might confer an increased susceptibility to breast cancer and contribute to aggressive phenotypic characteristics.

Glyoxalase I Ala111Glu gene polymorphism: no association with breast cancer risk but correlated with absence of progesterone receptor.

The aim of the present study was to evaluate the association between the Glyoxalase I (GLOI) Ala111Glu polymorphism and breast cancer risk among the major Malaysian ethnic groups, the Malays, Chinese and Indians, as well as clinico‐pathological characteristics of these patients. Genotyping of GLOI gene was performed on blood samples obtained from 387 patients and 252 normal healthy women who had no history of any malignancy using the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. The genotype and allele frequencies of GLOI polymorphism were not significantly different between the patients and normal individuals among the Malays (P= 0.721, 0.402), Chinese (P= 0.208, 0.079) and Indians (P= 0.612, 0.349), respectively. The Malay, Chinese and Indian women who were Glu/Glu homozygotes (P= 0.419, 0.093, 0.367), Ala/Glu heterozygotes (P= 0.648, 0.182, 0.402) and carriers of Glu allele (P= 0.402, 0.079, 0.349), respectively, were not associated with breast cancer risk. The Glu allele genotype was significantly associated with absence of progesterone receptor (P= 0.036). Thus, the polymorphic variant of the GLOI gene might not be a useful genetic marker to identify Malaysian Malay, Chinese or Indian women who could be at greater risk of developing breast cancer.