Anna Sobczuk

Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer.

The RAD51 protein and its paralog, XRCC3, play an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination. Since DSBs may contribute to the pathogenesis of breast cancer and variability in DNA repair genes may be linked with some cancers, we performed a case-control study (135 cases and 175 controls) to check the association between the genotypes of the Thr241Met polymorphism of the XRCC3 gene and the 135G>C polymorphism of the RAD51 gene and breast cancer occurrence and progression. Genotypes were determined in peripheral blood lymphocytes by RFLP-PCR. We did not find any association between either polymorphism singly and breast cancer occurrence. Both polymorphisms were not related to tumor size, estrogen and progesterone receptors status, cancer type and grade. However, the Thr241Met genotype of the XRCC3 polymorphism slightly increased the risk of local metastasis in breast cancer patients (OR 2.56, 95% CI 1.27-5.17). The combined Thr241Met/135G>C genotype decreased the risk of breast cancer occurrence (OR 0.22, 95% CI 0.08-0.59). Our results suggest that the variability of the DNA homologous recombination repair genes RAD51 and XRCC3 may play a role in breast cancer occurrence and progression, but this role may be underlined by a mutual interaction between these genes.

Association between sorbitol dehydrogenase gene polymorphisms and type 2 diabetic retinopathy

Diabetic retinopathy (DR) may affect 98% of diabetic patients, but its aetiology is poorly understood. Besides glycaemic exposure, genetic factors likely contribute to the onset of DR. The polyol pathway, including aldose reductase and sorbitol dehydrogenase (SDH), can be activated under hyperglycaemic conditions. In our work we searched for an association between the C-1214G and G-888C polymorphisms of the SDH gene promoter and the occurrence and progression of type 2 DR. Two hundred and fifteen unrelated individuals with type 2 diabetes mellitus (T2DM) were divided into three groups: without DR, with non-proliferative diabetic retinopathy (NPDR) and with proliferative diabetic retinopathy (PDR). Genotypes of the C-1214G (rs2055858) and G-888C (rs3759890) polymorphisms of the SDH gene were determined with DNA from the peripheral blood lymphocytes of patients by restriction fragment length polymorphism and allele-specific PCR, respectively. The genotype distributions were contrasted by the chi(2) test and the significance of the polymorphism was assessed by multiple logistic regression producing odds ratios (ORs) and 95% confidence intervals (CIs). We found an association (OR 1.73, 95% CI 1.06-2.83) between NPDR and the G allele of the G-888C polymorphism. There was no association between NPDR and the other polymorphisms of the SDH gene. No differences were found in the distributions of these polymorphisms between patients with PDR and those with NPDR. A weak association (OR 2.0, 95% CI 1.29-3.07) was found between DR and the G allele of the G-888C polymorphism. Analysis of the combined genotypes (haplotypes) of both polymorphisms revealed associations between the C/G-C/G genotype and NPDR (OR 2.95, 95% CI 1.07-8.13) as well as DR in general (OR 2.91, 95% CI 1.15-7.36). The G-888C polymorphism of the SDH gene may be associated with the onset of DR rather than with its progression, and its effect may be strengthened by the interaction with the C-1214G polymorphism, but this association is rather weak and requires further study.

Polymorphism of the ERα and CYP1B1 genes in endometrial cancer in a Polish subpopulation

Aim:  Metabolic activation of estrogens may play a role in endometrial carcinogenesis; and polymorphism of the genes (whose product is involved in this process) may be associated with the modulation of the risk of endometrial cancer. CYP1B1 plays a major role in the metabolism of estrogens, which must firstly bind their receptors, estrogen receptor alpha (ERα) or ER beta. In the present study we investigated the association of two polymorphisms of the CYP1B1 gene (Arg48Gly [142C > G] and Leu432Val [4326C > G]) and a polymorphism of the ERα gene (975C > G) as well as a combination between them with endometrial cancer occurrence.

New classification system of endometrial hyperplasia WHO 2014 and its clinical implications

Endometrial hyperplasia (EH) is a pathological condition characterised by hyperplastic changes in endometrial glandular and stromal structures lining the uterine cavity. Endometrial hyperplasia, particularly with atypia, is a significant clinical concern because it can be a precursor of endometrial cancer. Accurate diagnosis of precancerous lesions of the endometrium and exclusion of coexisting endometrial carcinomas are absolutely required for the optimal management of patients. The classification of endometrial hyperplasia has had numerous terminology. According to the classification of WHO94, based on glandular complexity and nuclear atypia, EH is divided into four groups: non-atypical endometrial hyperplasia (simple, complex) and atypical endometrial hyperplasia (simple, complex). Estimated risk of progression of atypical hyperplasia to endometrial cancer is 8-29%. The American College of Obstetricians and Gynaecologists and the Society of Gynaecological Oncology states that endometrial intraepithelial neoplasia (EIN) classification is superior to the World Health Organisation (WHO 94) classification for histology of endometrial hyperplasia. However, the WHO classification system remains the most commonly used and reported in existing literature. The new classification, WHO 2014, accepted by the International Society of Gynaecological Pathologists, divided hyperplasia into two groups: benign hyperplasia and atypical hyperplasia/endometrial intraepithelial neoplasia (EIN). The WHO 2014 schema is more likely to successfully identify precancerous lesions than the WHO94 classification.

Genomic imbalance in endometrial hyperplasia and cancer

Endometrial cancer belongs to the most frequently diagnosed malignant neoplasms of female genital organs, and its incidence is steadily growing. For the timebeing, no chromosomal aberrations have been determined unequivocally, which would be specific for the particular stages of endometrial hyperplasia and neoplastic transformation development. The goal of the undertaken studies was an identification of the earliest and specific genetic changes, which could be attributed to an increased risk of neoplastic transformation in a group of patients with endometrial hyperplasia plus the characteristics of genetic changes associated with the mature form of neoplasm. The study involved forty-four (44) patients, including five (5) histopathologically unconfirmed hyperplasia, twenty-six (26) with histopathologically confirmed endometrial hyperplasia and thirteen (13) with diagnosed endometrial cancer. The applied aCGH (array Comparative Genomic Hybridisation) method enabled selection of a few chromosomal regions which indicated a higher incidence of chromosomal rearrangements than in the control group. The study included also an evaluation of the frequency of mutations of the genes specific for neoplastic transformation development, the genes at chromosomal loci, which most frequently presented with genomic imbalance. In cases without hyperplasia, changes were diagnosed, described as CNVs (Copy Number Variations), which occurred with varying prevalence in the genome of the population of healthy subjects. Significant genomic imbalance was identified in 26 (100%) patients with diagnosed hyperplasia and in 11 (84.6%) of the patients with diagnosed endometrial cancer. Also other, till now unreported changes were found, localised at characteristic regions of the genome.