Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory. In total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA). A pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR. In our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.

Eur J Breast Health AVES | Copyright © 2017 Türkiye Meme Hastalıkları Dernekleri Federasyonu |

Breast cancer is the most common type of cancer and the leading cause of cancer related deaths in women in Turkey, as elsewhere around the world. However, detailed and systematic demographics, data on clinical and pathological characteristics, and treatment were largely unavailable in Turkey until now. This paper is intended to provide an analysis of clinical and pathological data on women registered in the National Breast Cancer Database (Ulusal Meme Kanseri Veri Tabanı [UMKVT]), established within Turkish Federation of Breast Diseases Societies (TMHDF) and available for use in Turkey since 2005. Clinical and pathological data on breast cancer patients registered online in the database from May 01, 2005 to May 01, 2011 were investigated. Parameters examined in patients included age, menopausal status, distribution of clinical and pathological stage, histological type, tumor diameter, histological grades, regional lymphatic stage, estrogen (ER), progesterone (PR), HER-2 receptors and molecular subtypes. Analysis results of these parameters were compared with literature data and discussed. A total of 13,240 patients with breast cancer since April 07, 1992 were included in the study, and 99% of them were female. Female breast cancer patients whose requisite parameters had been completely entered in the database were included in the analysis. The mean age was 51.6 years (±12.6; range 12-97), 17% of them were younger than 40 years of age, and 45% were premenopausal. According to an analysis of age groups at diagnosis, the frequency of cancer peaked at the 45 - 49 age group with 16.7%, declining to 7.6% in the 65-69 age group, and then rose again. Most of the patients (78.7%) had invasive ductal, 7.8% were invasive lobular cancers, 9.8% were invasive mixed cancers (invasive ductal + invasive lobular), and 4% were other histological types (e.g. inflammatory, intracystic papillary, mucinous, etc.), respectively. Half of them (50%) had grade III histology. According to an analysis of pathological stages of all breast cancers (stage 0 - IV), 5% were stage 0, 27% were stage I, 44% were stage II, 21% were stage III, and 3% were stage IV breast cancer, respectively. The mean tumor diameter was 2.5 cm (±1.6; range 0.1-20 cm). The rates of lymphatic stages were pN0 50%, pN1 28%, pN2 15%, and pN3 7%, respectively. ER, PR, and HER-2 receptors were positive in 70%, 59%, and 23% of patients. A subtype analysis of tumors showed that 62% were type luminal A. This was followed by subtypes luminal B (15%), triple negative (15%), and HER-2 positive (8.5%). As a conclusion patients with breast cancer in our breast cancer registry program were younger, and had more advanced disease, and worse prognostic factors than patients in developed countries.

High expression of immune checkpoint receptors (ICRs) in the tumor microenvironment regulates the anti-tumor response. In this study, the differential expressions of ICRs on tumor-infiltrating lymphocytes (TILs) in patients with early-stage breast cancer were investigated.The study included 32 patients who underwent surgery with a diagnosis of early-stage breast cancer between September 2018 and March 2020. TIL isolation was performed using a MACS tumor separation device and tumor separation kit. PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT expression of cytotoxic T and natural killer (NK) cells on TILs and peripheral blood lymphocytes (PBLs) were determined by flow cytometry.Patients with a high Ki-67 index, high TIL density, and HER-2 positivity were more likely to have increased CD16⁺CD56^dim NK cells on TILs. Patients with T2 tumors were more likely to have increased expression of PD-1, LAG-3, and TIGIT on tumor-infiltrating CD8⁺ cytotoxic T cells than those with T1 tumors. PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 expression of CD8⁺ T and CD16^-CD56^bright NK cells in TILs showed significant positive correlations with each other. PD1⁺CD8⁺, TIGIT⁺CD16⁺, and CTLA-4⁺CD56⁺ cells in PBLs and TILs were found to be negatively correlated, whereas only TIM-3⁺ expression of CD8⁺ T and CD16⁺CD56^dim cells in PBLs and TILs showed positive correlations.Our results suggest that CD16⁺CD56^dim NK cells on TILs may play a major role in the immune response against HER2-positive or highly proliferating breast tumors in patients with early-stage breast cancer. Furthermore, various ICRs were found to be highly co-expressed with each other on TILs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT. These receptors may synergistically suppress the response to the tumor, which may trigger immune escape mechanisms in the early stage of carcinogenesis. However, ICR expressions other than TIM3 on PBLs were not found to accompany their counterparts on TILs.

Breast cancer has been increased in developing countries, but there are limited data for breast cancer risk factors in these countries. To clarify the risk for breast cancer among the Turkish women, an university hospital based nested case-control study was conducted. Between January 2000 and December 2006, a survey was prospectively conducted among women admitted to clinics of Istanbul Medical Faculty for examination and/or treatment by using a questionnaire. Therefore, characteristics of patients diagnosed with breast cancer (n = 1492) were compared with control cases (n = 2167) admitted to hospital for non-neoplastic, non-hormone related diseases. Breast cancer risk was found to be increased in women with age (≥ 50) [95% confidence interval (CI) 2.42–3.18], induced abortion (95% CI 1.13–1.53), age at first birth (≥ 35) (95% CI 1.62–5.77), body mass index (BMI ≥ 25) (95% CI 1.27–1.68), and a positive family history (95% CI 1.11–1.92). However, decreased breast cancer risk was associated with the duration of education (≥ 13 years) (95% CI 0.62–0.81), presence of spontaneous abortion (95% CI 0.60–0.85), smoking (95% CI 0.61–0.85), breast feeding (95% CI 0.11–0.27), nulliparity (95% CI 0.92–0.98), hormone replacement therapy (HRT) (95% CI 0.26–0.47), and oral contraceptive use (95% CI 0.50–0.69). On multivariable logistic regression analysis, age (≥ 50) years (OR 2.61, 95% CI 2.20–3.11), induced abortion (OR 1.66, 95% CI 1.38–1.99), and oral contraceptive use (OR 0.60, 95% CI 0.48–0.74) were found to be associated with breast cancer risk as statistically significant independent factors. These findings suggest that age and induced abortion were found to be significantly associated with increased breast cancer risk whereas oral contraceptive use was observed to be associated with decreased breast cancer risk among Turkish women in Istanbul.