BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients.

BRCA1/BRCA2 genes were screened in 117 patients with breast cancer by sequencing. Fourteen percent of patients tested positive for BRCA1/BRCA2 mutations. Four frame shift mutations, four pathogenic missense mutations, and 25 different sequence variations were detected. BRCA mutation positivity was significantly associated with Ki67 (p = .001). BRCA protein expressions were decreased in the patients harboring important mutations and polymorphisms (BRCA1;P508 stop, V1740G, Q1182R, Q1756P and BRCA2;V2466A) related with disease. Our findings contribute significantly to the types of germline BRCA1/BRCA2 mutations and their biological effects in Turkish women. These data could help guide the management of BRCA1/BRCA2 mutation-carrying patients when considering breast-conserving therapy.

Expression status of let-7a and miR-335 among breast tumors in patients with and without germ-line BRCA mutations.

The genetic factors of cancer predisposition remain elusive in the majority of familial and/or early-onset cases of breast cancer (BC). This type of BC is promoted by germ-line mutations that inactivate BRCA1 or BRCA2. On the other hand, recent studies have indicated that alterations in the levels of miRNA expression are linked to this disease. Although BRCA1 and BRCA2 gene mutations have been reported to commonly lead to alterations in genes that encode cancer-related proteins, little is known regarding the putative impact of these mutations on noncoding miRNAs. In the present study, we aimed to determine whether miRNA dysregulation is involved in the pathogenesis of BRCA-mutated BC. An expression analysis of 14 human miRNAs previously shown to be related to BC diagnosis, prognosis, and drug resistance was conducted using tissues from 60 familial and/or early-onset patients whose peripheral blood samples had been screened for BRCA1 and BRCA2 mutations through sequence analysis. Let-7a and miR-335 expression levels were significantly downregulated in the tumors of patients with a BRCA mutation compared with those of patients without a BRCA mutation (P = 0.04 and P = 0.02, respectively). Our results defined the associations between the expression status of let-7a and miR-335 and BRCA mutations. The expression analysis of these miRNAs might be used as biomarkers of the BRCA mutation status of early-onset and/or familial BC.

Investigation of the Relationship Between Tumor Microenvironment and Prognostic Parameters in Invasive Breast Carcinomas of No Special Type: A Retrospective Analysis.

OBJECTIVE: The tumor microenvironment is a heterogeneous and constantly changing territory that plays an active role in tumor formation and progression. It constantly interacts with tumor cells, plays an active role in tumor development, and even appears as a parameter of prognostic importance, and the importance of the tumor microenvironment in breast cancer has been emphasized by recent studies. In this study, we aimed to retrospectively evaluate the relationship between the tumor microenvironment and prognostic parameters in invasive breast carcinomas of no special type. MATERIAL AND METHODS: A total of 271 cases diagnosed as invasive breast carcinoma of no special type from resection materials in our center between 2007 and 2015 were included in the study. Hematoxylin-eosin stained slides with a thickness of 4-5 micrometers were evaluated in terms of tumor infiltrating lymphocytes, peritumoral and intratumoral desmoplastic reaction, intratumoral and peritumoral tumor budding, stromal features, and tumor growth pattern. RESULTS: When parameters related to the tumor microenvironment were compared with other prognostic parameters, there was a significant relationship between TILs and tumor grade, size, stage, immunohistochemical subgroup and Ki-67 proliferation index. A significant relationship was detected between intratumoral stromal reaction and tumor grade, size, molecular subgroup and the Ki-67 proliferation index (p < 0.05). When stroma and other prognostic parameters were compared, tumors with desmoplastic stroma had higher grades and higher Ki-67 proliferation indexes, and they were observed more frequently in the triple negative molecular subgroup. CONCLUSION: We believe that including parameters related to tumor microenvironment in breast cancer reports, which hold a prognostic and predictive importance, will contribute to patient management. Considering the fact that these can be easily evaluated from routinely used hematoxylin-eosin stained slides, this does not cause additional costs or excessive time loss.

Evaluation of incidence and histolopathological findings of breast lesions in reduction mammoplasty specimens: Uludag University experience.

OBJECTIVE: To report the incidence of benign, pre-cancerous and malignant lesions in reduction mammoplasty specimens. METHODS: The retrospective study was conducted at the Uludag University, Bursa, Turkey and comprised data of 264 patients who underwent bilateral breast reduction between 2004 and 2009. Operative reports and pathological findings of all patients were reviewed. Patients were divided into three age groups with reference to the hormonal characteristics: girls and women between 13 and 35 years constituted group 1; women older than 35 and younger than 50 years old were clustered in group 2; and women over 50 years formed group 3. Descriptive statistics were applied. RESULTS: Fibrocystic disease was the most common (n=402; 76.13%) lesion in all groups. Proliferative lesions such as intraductal epithelial hyperplasia and atypical ductal hyperplasia were each found in 0.4% (n=2) cases. There were 2(0.4%) cases with invasive ductal carcinoma, and 1(0.2%) case with ductal carcinoma in situ. All malignant tumours were found in patients over 50 years of age. CONCLUSION: Microscopic examination of macroscopically normal breast tissue from breast reduction specimens may provide noteworthy pathological findings. Histological sampling of reduction mammoplasty specimens gave rise to the early detection of occult neoplastic breast lesions.

A Multicenter Study of Genotype Variation/Demographic Patterns in 2475 Individuals Including 1444 Cases With Breast Cancer in Turkey.

Objective: Breast cancer (BC) is the most common cancer type in women and may be inherited, mostly in an autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and analysis of two genes, BRCA1 and BRCA2, which are strongly associated with BC, are included in these criteria. The aim of this study was to compare BC index cases with non-BC individuals in terms of genotype and diagnostic features to investigate the genotype/demographic information association. Materials and Methods: Mutational analyses for the BRCA1/BRCA2 genes was performed in 2475 individuals between 2013-2022 from collaborative centers across Turkey, of whom 1444 with BC were designated as index cases. Results: Overall, mutations were identified in 17% (421/2475), while the percentage of mutation carriers in cases of BC was similar, 16.6% (239/1444). BRCA1/BRCA2 gene mutations were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic cases. Mutations in BRCA1 were found in 4.9%, whereas 12% were in BRCA2 (p<0.05). Meta-analyses were performed to compare these results with other studies of Mediterranean-region populations. Conclusion: Patients with BRCA2 mutations were significantly more common than those with BRCA1 mutations. In sporadic cases, there was a lower proportion with BRCA1/BRCA2 variants, as expected, and these results were consistent with the data of Mediterranean-region populations. However, the present study, because of the large sample size, revealed more robust findings than previous studies. These findings may be helpful in facilitating the clinical management of BC for both familial and non-familial cases.

Surgical Trends in Breast Cancer in Turkey: An Increase in Breast-Conserving Surgery.

PURPOSE: Breast cancer is the most frequent cancer in women, and there is a great variability in surgical practice for treating that cancer in different countries. The aims of this study were to analyze the effect of guidelines from the Turkish Federation of Breast Diseases Societies on academic institutions that have breast centers and to evaluate surgical practice in Turkey in 2018. PATIENTS AND METHODS: Between January and March 2019, a survey was sent to breast surgeons who were working in breast centers in academic institutions. The sampling frame included 24 academic institutions with breast centers in 18 cities in Turkey to evaluate interdisciplinary differences among breast centers and seven regions in Turkey regarding patients' choices, surgical approaches, and academic institutions. RESULTS: All surgeons responded to the survey, and all 4,381 patients were included. Most of the surgeons (73.9%) were working in a breast center. Multidisciplinary tumor boards were performed in 87% of the breast centers. The average time between clinical evaluation and initiation of treatment was 29 days; the longest time was in Southeast Anatolia (66 days). Only 6% of patients had ductal carcinoma in situ. Sentinel lymph node biopsy was available in every region across the country and was performed in 64.5% of the patients. In 2018, the overall breast-conserving surgery rate was 57.3% in Turkey, and it varied from 72.2% in the Black Sea region to 33.5% in Central Anatolia (P < .001). Oncoplastic breast surgery options were available at all breast centers. However, 25% of the breast centers from the Black Sea region and half the breast centers from Eastern Anatolia and the Mediterranean region did not perform this type of surgery. CONCLUSION: Increasing rates of nonpalpable breast cancer and decreasing rates of locoregional recurrences favored breast-conserving surgery, especially in developed countries. Guidelines from the Turkish Federation of Breast Diseases Societies resulted in more comprehensive breast centers and improved breast health in Turkey.

A case of extensive ductal carcinoma in situ and sclerosing adenosis with metastasis on sentinel lymph node.

INTRODUCTION: Sclerosing adenosis is a form of adenosis characterized by lobulocentric architecture, glandular and stromal proliferation in which the stromal component compresses and distorts the glandular structures. Atypical epithelial proliferations such as atypical lobular hyperplasia, lobular carcinoma in situ, and ductal carcinoma in situ may accompany areas of sclerosing adenosis. We present a case of ductal carcinoma in situ and sclerosing adenosis with metastatic carcinoma on sentinel lymph node. CASE DESCRIPTION: A 40-year-old woman presented with a palpable mass in her left breast. Radiologic studies showed a lesion suggesting malignancy in the left breast and atypical lymph node in the left axillary region. Left lumpectomy and sentinel lymph node biopsy was performed. Histopathologic examination revealed lobulocentric lesions with glandular proliferation and hyalinizing stroma in between. Foci of high-grade cribriform and solid type ductal carcinoma in situ were observed. Sentinel lymph node biopsy showed micrometastasis in one lymph node section. Based on these findings, the patient was diagnosed with high-grade ductal carcinoma in situ with sclerosing adenosis. However, the presence of micrometastasis in the lymph node suggested occult invasion that we were not able to detect. CONCLUSION: Ductal carcinoma in situ with sclerosing adenosis can mimic invasive carcinoma both radiologically and histologically. It should be kept in mind that there may be occult invasive carcinoma in patients with ductal carcinoma in situ whether the lesion is accompanied by sclerosing adenosis or not. Multiple sections and immunohistochemical studies can be of help.

Carcinoma originating from aberrant breast tissue. A case report and review of the literature.

Carcinoma arising from ectopic breast tissue, either supernumerary breast or aberrant breast tissue, is extremely rare. Carcinoma occurs more frequently in the ectopic breast tissue of the axilla than in extra-axillary ectopic breast tissue. Here we report a case of an invasive lobular carcinoma arising from extra-axillary ectopic breast tissue and presenting as a subcutaneous nodule.

Synchronous breast cancer in spouses.

Breast cancer in both spouses is extremely rare. There are 7 metachronous cases and 1 synchronous case in the English literature. No case has been reported in which 1 of the spouses had bilateral breast cancer. In this paper, we report a synchronous pair of cases where 1 of the spouses (wife) had bilateral breast cancer and the other (husband) had breast cancer.

Factors influencing axillary node metastasis in breast cancer.

AIMS AND BACKGROUND: The status of the axillary lymph nodes at the time of diagnosis has been accepted as one of the most important prognostic factors for the overall and disease-free survival of patients with breast cancer. The aim of our study was to determine which factors influence axillary node involvement in invasive breast cancer. METHODS: The data presented here were obtained from 344 patients who were treated for invasive breast cancer at the Department of Radiation Oncology, Uludag University Medical College, Bursa, Turkey. Possible prognostic factors were categorized as patient related and tumor related. The Mann-Whitney U test was used for univariate analysis and logistic regression was used for multivariate analysis. RESULTS: In univariate analysis, a familial cancer history (P = 0.0042), age < 40 years (P = 0.0276), higher T stage (P < 0.0000), nipple involvement (P = 0.0345), skin involvement (P = 0.0270), perineural invasion (P = 0.0231), and lymphatic vessel invasion (P < 0.0000) were correlated with increased axillary node involvement. A higher incidence of > or = 4 involved lymph nodes was associated with higher T stage (P = 0.0004), nipple involvement (P = 0.0292), presence of an extensive intraductal component (P = 0.0023), skin involvement (P = 0.0008), perineural invasion (P = 0.0523), and lymphatic vessel invasion (P < 0.0000) in univariate analysis. In multivariate analysis, age < 40 years (P = 0.0454), cancer history within the family (P = 0.0024), higher T stage (P = 0.0339), lymphatic vessel invasion (P = 0.0003), and perineural invasion (P = 0.0408) were found to be independent factors for axillary lymph node positivity. Age < 40 years (P = 0.0221), perineural invasion (P = 0.0408), and an extensive intraductal component (P = 0.0132) were associated with an increased incidence of > or = 4 involved nodes in the logistic regression analysis. In patients with breast cancer, the incidence of axillary lymph node involvement was independently influenced by age < 40 years, presence of cancer history within the family, higher T stage, lymphatic vessel invasion, and perineural invasion. CONCLUSIONS: In conclusion, absence of familial cancer history, presence of lymphatic vessel invasion, higher T stage, and age below 40 years independently increased the risk of axillary node involvement. Presence of perineural invasion and lymphatic vessel invasion, age below 40, and an extensive intraductal component of more than 25% independently affected the risk of having > or = 4 nodes involved. Patients characterized by these factors may be classified into a higher risk group for nodal involvement, but more data are needed to define factors that can help in the decision-making regarding the omission of axillary treatment.

Incidentally Discovered Extensive Squamous Metaplasia within Borderline Phyllodes Tumor: Presentation of a Rare Tumor.

Phyllodes tumors are uncommon biphasic fibroepithelial neoplasms of breast, comprising less than 1% of all breast neoplasms. We therefore aimed to present the case with its microscopic findings. In this article, we report a 59-year-old female admitted to the general surgery department with a rapidly, enlarging, palpable mass in right breast. After histopathological examination, it was diagnosed as borderline phyllodes tumor with extensive squamous metaplasia. Metaplastic changes are infrequent in the stromal and epithelial component of these tumors. Extensive squamous metaplasia within phyllodes tumor is rare and may occur in benign, borderline and malign subtypes.

Expression and clinical significance of miRNAs that may be associated with the FHIT gene in breast cancer.

The dysregulation of miRNA expression has frequently been observed in breast cancer. Therefore, we investigated the expression profile of miRNAs that may be associated with expression of the FHIT gene in breast cancer and assessed their clinicopathological significance. The expression levels of miR-143, miR-663a, miR-668, miR-922 and FHIT were analyzed in normal and malignant breast tissues from 65 patients with breast cancer. We studied the correlation between the expression of miR-143, miR-663a, miR-668, miR-922 and FHIT and the clinicopathological features presented by the patients. The expression levels of the miRNAs and FHIT were downregulated in breast cancer tissue. The expression levels of miR-143, miR-663a and miR-668 were significantly reduced in FHIT downregulated tumors. miR-668 expression was also significantly altered relative to FHIT down- and up- regulated tumor tissues. Reduced miR-663a expression was statistically associated with high-grade ER/PR (+) status, benign reactive hyperplasia, lymph-node metastasis, in-situ component >25% and Ki 67>15% compared with non-tumor tissues. Additionally, reduced miR-668 expression was significantly different between tumors with and without lymph-node metastasis. miR-668 may play an important role in breast cancer development and progression by regulating the expression of FHIT. Furthermore, miR-668 and miR-663a may be potential prognostic biomarkers for breast cancer.

Circulating miR-195 as a Therapeutic Biomarker in Turkish Breast Cancer Patients.

BACKGROUND: Dysregulation of miRNA expression may be used as a biomarker for specific tumours because it may contribute to development of cancer. Circulating miRNA profiles have been highlighted for their potential as predictive markers in heterogeneous diseases such as breast cancer. In the literature, there is evidence that miR-195 levels are differentially expressed pre- and post-operative periods in breast cancer patients. At the same time, miRNA expression levels may vary because of ethnic origins. This study aimed to determine expression levels and potential roles of miR-195 in Turkish breast cancer patients. MATERIALS AND METHODS: The expression patterns of miR-195 were initially examined in breast cancer tissues (luminal A and B type) (n=96). Subsequently, blood samples were prospectively collected from preoperative and postoperative Turkish breast cancer patients and disease free controls. Total RNA was isolated, and the expression level of miR-195 was quantified by real-time PCR. RESULTS: We found that miR-195 level was altered in Turkish breast cancer patients, with down-regulation evident in breast cancer tissues compared to normal adjacent specimens. Furthermore, circulating levels of miR- 195 was significantly decreased in post-operative blood samples compared with pre-operative levels (p=0.01 and <0.05). However, miR-195 was significantly increased in pre-operative blood samples of the luminal B type (p= 0.04 and <0.05). CONCLUSIONS: This study represents the first report of a miR-195 expression profile in Turkish breast cancer patients. Our data suggests that miR-195 levels might be a clinically useful biomarker in the earliest stage of Turkish breast cancer patients.

BRCA mutations cause reduction in miR-200c expression in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer (BC). Over the recent years, miRNA expression studies have been providing certain detailed overview that aberrant expression of miRNAs is associated with TNBC. Although TNBC tumors are strongly connected with loss of function of BRCA genes, there is no knowledge about the effect of BRCA mutation status on miRNA expressions in TNBC cases. The aims of this study were to evaluate the expression profile of miRNAs that plays role in TNBC progression and the role of BRCA mutations in their regulation. The expression level of BC associated 13 miRNAs was analyzed in 7 BRCA mutations positive, 6 BRCA mutations negative TNBC cases and 20 non-tumoral tissues using RT-PCR. According to RT2 Profiler PCR Array Data Analysis, let-7a expression was 4.67 fold reduced in TNBCs as compared to normal tissues (P=0.031). In addition, miR-200c expression was 5.75 fold reduced in BRCA mutation positive TNBC tumors (P=0.005). Analysis revealed a negative correlation between miR-200c and VEGFA expressions (r=-468). Thus, miR-200c may be involved in invasion and metastasis in TNBC cases with BRCA mutation. In this study we provide the knowledge on the first report of association between microRNA-200c and BRCA mutations in TNBC. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for TNBC treatment and new directions for the development of anticancer drugs.

Association of miR-1266 with recurrence/metastasis potential in estrogen receptor positive breast cancer patients.

The Homeobox B13 (HOXB13):Interleukin 17 Receptor B (IL17BR) index of estrogen receptor (ER)-positive breast cancer (ER (+) BC) patients may be a potential biomarker of recurrence/ metastasis. However, effects of microRNA (miRNA) binding to the 3' untranslated region (3 ?UTR) of HOXB13 and IL17BR and its function on recurrence/metastasis in ER (+) BC remains elusive. The aims of this study were to determine the expression of miRNAs that bind to 3 ?UTR of HOXB13 and IL17BR in ER (+) BC patients and asess the effects of these miRNAs on recurrence/metastasis. The expression profiles of HOXB13 and IL17BR were evaluated using RT- PCR in tumors and normal tissue samples from 40 ER (+) BC patients. The expression level of 4 miRNAs, which were predicted to bind the 3 ?UTR of HOXB13 and IL17BR using TargetScan, microRNA.org and miRDB online databases, were further evaluated with RT-PCR. Our findings demonstrated that high miR-1266 levels might be significant prognostic factor for recurrence/metastasis occurrence (3.05 fold p=0.004) and tamoxifen response (3.90 fold; p=0.2514) in ER (+) BC cases. Although we suggest that modulation of miR-1266 expression may be an important mechanism underlying the chemoresistance of ER (+) BC, advanced studies and validation are required.

Acquired lymphangiectasis after breast conservation treatment for breast cancer: report of a case.

Acquired lymphangiectasis is a dilatation of lymphatic vessels that can result as a complication of surgical intervention and radiation therapy for malignancy. Acquired lymphangiectasis shares clinical and histological features with the congenital lesion, lymphangioma circumscriptum. Diagnosis and treatment of these vesiculobullous lesions is important because they may be associated with pain, chronic drainage, and cellulitis. We describe patient who had these lesions after treatment for cancer. Although a number of treatment options are available, we have found cryosurgery and electrocautery to be particularly effective.

Traumatic pelvic hydatid cyst rupture: report of a case.

Secondary peritoneal echinococcosis is one of the important complications of cyst hydatid disease. Although many ruptured hydatid cysts of a primary organ have been reported, there is only one case of peritoneal hydatid cyst rupture in the literature. In this case report we present a 25 year-old male patient, who had been operated for hydatid cyst of the liver four years ago and had pelvic hydatid cyst rupture due to blunt abdominal trauma.

Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer.

Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron- exon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.