Evaluation of Breast Skin/Nipple-Areolar Complex Sensation and Quality of Life after Nipple-Sparing Mastectomy Followed by Reconstruction.

Background and Objectives: Sensation of the breast skin and nipple-areolar complex (NAC) is commonly assumed to be diminished or completely absent following nipple-sparing mastectomy (NSM) with implant- or expander-based reconstruction. The purpose of this cohort study was to evaluate breast skin and NAC long-term touch pressure sensibility, from 1 month to 1 year, after NSM followed by reconstruction with an implant or expander, and patient quality of life (QoL), hypothesizing that sensibility may diminish with a small progressive return throughout the postoperative period. Materials and Methods: This was achieved by performing sensation tests using Semmes-Weinstein monofilaments (SWM) in nine predefined points of the breast and NAC, a two-point discrimination test (TPD) in the four quadrants of the breast, and QoL assessment using the BREAST-Q. We evaluated 42 patients in Pauls Stradins Clinical University Hospital, with a total of 66 breasts, who underwent NSM between 2021 and 2023, performing the breast sensation tests before surgery and postoperatively at 1/3/6 months and 1 year. The BREAST-Q was administered to assess patient satisfaction and well-being. Results: Our results reflect a decline in breast skin and NAC sensation in the 1-month evaluation after NSM (mean: 4.67) when compared to the assessment before surgery (mean: 2.57), with a small progressive return reflected in the 3 months (mean: 3.79), 6 months (mean: 3.68), and 1-year evaluations (mean: 3.14). The following were the mean scores obtained from the BREAST-Q: Psychosocial Well-being (mean: 66), Sexual Well-being (mean: 50), Satisfaction with Breasts Pre-OP (mean: 58), satisfaction with breast reconstruction (mean: 52), Satisfaction with Implants, Satisfaction with nipple reconstruction, Physical Well-being Chest, Adverse effects of radiation, and Satisfaction with Information. Conclusions: This study confirms that sensibility diminishes after this procedure, as observed when comparing the sensation evaluation results before the operation with the 1-month evaluation, reflecting a small progressive return in the following months.

Novel Nipple Reinnervation Technique Using N. Suralis Graft.

Following nipple-sparing mastectomy (NSM), patients commonly experience significant impairment or total loss of nipple sensitivity, which negatively impacts the patients' quality of life, whereas patients who retain nipple sensation postoperatively experience enhanced physical, psychosocial, and sexual well-being. Reinnervation techniques such as nerve allografting have been utilized to retain sensation. Despite the benefits of nerve allografts, such as lack of donor site morbidity, ease of use, and potentially shorter surgery time, there are shortcomings, such as the cost of commercially available acellular nerve allografts, and, most importantly, decreased sensory and motor function recovery for acellular nerve allografts with a diameter greater than 3 mm or a length greater than 50 mm. We present a technique where we performed immediate implant-based breast reconstruction combined with nipple-areola complex reinnervation using an autologous nerve graft. Following the procedure, the patient had improved sensory outcomes in the reconstructed breast and good quality-of-life indices. This report highlights the potential for sural nerve autografts in restoring breast sensation following mastectomy.

Pathological complete response to neoadjuvant chemotherapy in triple negative breast cancer - single hospital experience.

BACKGROUND: Triple-negative breast cancer is a heterogeneous molecular subtype of BC. Pathological complete response (pCR) is an important surrogate marker for recurrence-free and overall survival. AIM OF STUDY: The aim of this study was to evaluate clinical and pathological factors that are associated with complete pathological response status in triple-negative breast cancer patients receiving neoadjuvant chemotherapy. MATERIALS AND METHODS: Eighty triple-negative breast cancer patients who underwent neoadjuvant chemotherapy followed by surgery at Pauls Stradins Clinical University Hospital between January 2018 and January 2020 were retrospectively analysed. Twenty-six patients (32.5%) were BRCA1/2 pathogenic variant carriers. RESULTS: A total of 32.5% (n = 26) of patients in all study groups and 57.7% (n = 15) of patients with BRCA1/2 pathogenic variants achieved pCR. Forty-seven patients received platinum-based neoadjuvant chemotherapy, and 19 patients (40.4%) achieved complete pathological response. Patients in the pCR group presented with significantly higher Ki-67 scores (p = 0.007), BRCA1/2 pathogenic variants (p = 0.001) and younger age (p = 0.02) than those in the non-pCR group. pCR did not significantly impact recurrence-free survival (RFS) or overall survival (OS). Multivariate analysis revealed that pretreatment N stage (clinical nodal status) was an independent prognostic factor for RFS and OS. CONCLUSIONS: BRCA1 pathogenic variants, high Ki67 score and young age were predictors of pathological complete response, while clinical nodal status predicted survival outcomes in triple-negative breast cancer.

Health-Related Quality of Life After Nipple-Sparing Mastectomy: Results From the INSPIRE Registry.

INTRODUCTION: Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to report the results of the INSPIRE registry assessing health-related quality of life (HRQoL) comparing baseline and 1-year follow-up, regarding surgical indications and chemotherapy (CT) received. METHODS: INSPIRE is a prospective database including women undergoing NSM and IBR from 18 countries. HRQoL was measured using EORTC QLQC30 and QLQ-BR23 before surgery and after 1 year. RESULTS: A total of 677 women were included, of whom 537 (79.3%) underwent TNSM and 140 (21.6%) RRNSM: in total, 806 NSM (556 TNSM and 250 RRNSM). Nipple involvement was present in 7.73% of TNSM and incidental carcinoma in 1.2% of the RRNSM group. Out of the overall 537 patients with systemic treatment, 177 (32.96%) received neoadjuvant chemotherapy (NCT) and 118 (21.92%) adjuvant chemotherapy (CT). A total of 227 patients (28.16%) developed at least one complication postoperatively, 164 (29.5%) in the TNSM group and 63 (25.2%) in the RRNSM group. The TNSM group improved in global health status and emotional functioning after 1 year. No differences were found when comparing HRQoL at 1 year between patients who received NCT and those who received adjuvant CT. The RRNSM group showed improvement in HRQoL, with better emotional functioning and fatigue after 1 year. CONCLUSIONS: This registry reports HRQoL findings after NSM. The impact of CT on worse HRQoL is independent from its timing. Patients with RRNSM showed an improved HRQoL at 1-year follow-up. Discussion of HRQoL outcomes with patients will facilitate the informed decision-making when considering NSM.

Pregnancy after breast cancer in BRCA1/2 mutation carriers.

BACKGROUND: Often young women affected with BRCA1/2 positive breast cancer have not finished or even not started their childbearing before the onset of the disease. The aim of our mini-review is to summarize state of art knowledge on pregnancy after breast cancer in BRCA1/2 carriers. METHODS: A broad review of the literature was conducted using MEDLINE (via PubMed) for relevant articles published. This review summarizes the impact of different cytotoxic agents on a fertility, fertility preservation, maternal and fetal prognosis after pregnancy in breast cancer survivors with BRCA1/2. CONCLUSION: According to the existing literature evidence pregnancy after therapy for breast cancer in BRCA carriers is safe for the mother and offspring, but patients' needs, oncofertility counseling and fertility-sparing strategy should be carefully planned before starting the cytotoxic treatment.

Ultrasound guided needle biopsy of axilla to evaluate nodal metastasis after preoperative systemic therapy in cohort of 106 breast cancers enriched with BRCA1/2 pathogenic variant carriers.

BACKGROUND: Aim of the study is to evaluate the role of ultrasound guided fine needle aspiration cytology (FNAC) in the restaging of node positive breast cancer after preoperative systemic therapy (PST). METHODS: From January 2016 - October 2020 106 node positive stage IIA-IIIC breast cancer cases undergoing PST were included in the study. 18 (17 %) were carriers of pathogenic variant in BRCA1/2. After PST restaging of axilla was performed with ultrasound and FNAC of the marked and/or the most suspicious axillary node. In 72/106 cases axilla conserving surgery and in 34/106 cases axillary lymph node dissection (ALND) was performed. RESULTS: False Positive Rate (FPR) of FNAC after PST in whole cohort and BRCA1/2 positive subgroup is 8 and 0 % and False Negative Rate (FNR) - 43 and 18 % respectively. Overall Sensitivity - 55 %, specificity- 93 %, accuracy 70 %. CONCLUSION: FNAC after PST has low FPR and is useful to predict residual axillary disease and to streamline surgical decision making regarding ALND both in BRCA1/2 positive and negative subgroups. FNR is high in overall cohort and FNAC alone are not able to predict ypCR and omission of further axillary surgery. However, FNAC performance in BRCA1/2 positive subgroup is more promising and further research with larger number of cases is necessary to confirm the results.

Allelic variants of breast cancer susceptibility genes PALB2 and RECQL in the Latvian population.

BACKGROUND: Large-scale case control studies revealed a number of moderate risk - low frequency breast cancer alleles of the PALB2 and RECQL genes. Some of these were reported as founder variants of Central and Eastern Europe. Based on highly similar founder variant spectra of the BRCA1 in Poland and Latvia, we decided to test the frequency of other common variants of moderate breast cancer risk - c.509_510delGA (rs515726124) and c.172_175delTTGT (rs180177143) of the PALB2 gene and c.1667_1667+3delAGTA variant of the RECQL gene in a breast cancer case-control series from Latvia to better understand the role of genes in susceptibility to breast cancer and their clinical significance. METHODS: The case-control study was performed based on an unselected breast cancer case group of 2480 women and a control group, including 1240 voluntary, to our knowledge unrelated, female donors without reported oncological disease. RESULTS: The calculated frequency for c.509_510delGA of the PALB2 gene in the case group is 0.35 and 0.00% in the control group, with respective relative risk (RR) 7.18 (CI 95% 0.37-138.75; p = 0.19). As for the PALB2 c.172_175delTTGT variant, the frequency in the case group of our study is 0.04%. In the control group of our study all individuals were homozygous for the wild-type allele, which lead to calculated RR = 1.50 (CI 95% 0.06-36.83; p-value = 0.80). There were no carriers of the RECQL variant c.1667_1667+3delAGTA identified in our case group and 2 heterozygotes were identified in the control group. The calculated RR = 0.26 (CI 95% 0.01-5.33; p-value = 0.38). CONCLUSION: Results obtained for the PALB2 gene variants are able to supplement evidence on the allele frequency in breast cancer patients from the region of Central and Eastern Europe. Based on our results we cannot confirm the contribution of the RECQL variant c.1667_1667+3delAGTA allele to breast cancer development.

Body mass index and nipple preservation are major contributors to satisfaction and aesthetic outcome rates after implant-based immediate breast reconstruction.

INTRODUCTION: Immediate breast reconstructions (IBR) have become an integral part of modern breast cancer management. However, in a small breast unit the spectrum of methods used for IBR could be limited, which could result in poorer results in some cases. The aim of the study is to evaluate the patient satisfaction and aesthetic outcome results in a breast unit where only implant-based IBR were performed. MATERIAL AND METHODS: During 2009-2016, 64 cases of implant-based IBR were performed in the university hospital. 55 patients completed the questionnaire and 38 underwent evaluation by a plastic surgeon. 33 skin-sparing and 22 nipple-sparing mastectomies were included. The study included 30 two-stage expander/implant and 25 direct-toimplant IBR cases. RESULTS: Overall satisfaction was reported by 89% of respondents. 93% were satisfied with appearance in clothes and 82% with appearance in a bra. There was a significant difference with satisfaction in nude appearance between groups with a removed (3%) and a spared nipple (46%). The plastic surgeon evaluated overall outcome as satisfactory in 61% and poor in 39%. Spearman coefficient showed a moderate negative correlation between body mass index (BMI) and aesthetic outcome (p = 0.02), as well as BMI and volume differences between breasts (p = 0.03). Patients evaluated their breast symmetry as satisfactory in 55%, and the plastic surgeon concluded the same in 55% of 38 cases. CONCLUSIONS: Most of the patients were satisfied with the aesthetic outcome of IBR. Nipple preservation considerably improved satisfaction rates. However, implant-based IBR revealed suboptimal cosmetic results in the subset of cases with increased BMI and other IBR methods should be considered in those cases.

Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review.

BACKGROUND: There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting. METHODS: A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review. RESULTS: Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies. CONCLUSION: The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.

High expression of miR-214 is associated with a worse disease-specific survival of the triple-negative breast cancer patients.

BACKGROUND: Hereditary triple-negative breast cancer patients have better recurrence-free survival than triple-negative sporadic ones. High expression of some of the miRNAs is related to worse overall and disease-free survival of triple-negative breast cancer patients. The attempt to associate expression level of some miRNA in triple-negative hereditary and sporadic breast cancers to disease specific survival was performed in this study. MATERIAL AND METHODS: Study group was made of 18 triple-negative breast cancer patients harboring the BRCA1 gene mutations and 32 triple-negative sporadic breast cancer patients. Quantitative amount of mir-10b, mir-21, mir-29a, mir-31, and mir-214 by real-time PCR was assessed. The disease-specific survival in relation of high and low levels of some of the miRNAs was analyzed using Log-rank (Mantel-Cox) test. RESULTS: MiR-214 showed significantly higher expression level in sporadic tissues than in hereditary ones (p = 0.0005). Triple-negative breast cancer patients with high level of miR-214 showed significantly worse disease-specific survival than patients with low level (p = 0.0314). CONCLUSIONS: Our finding suggests that miR-214 possibly could be used as a potential prognostic biomarker for triple-negative breast cancer patients.

Prostate cancer trends in Latvia during 1990-2012: incidence, prevalence, mortality, and survival rates.

BACKGROUND AND OBJECTIVE: Prostate cancer (PCa) is one of the most common form of cancer in males worldwide. One of the highest PCa-related mortality rates in the world is observed in Latvia. MATERIALS AND METHODS: Our study included male patients diagnosed with PCa between 1990 and 2012. We analyzed incidence, prevalence and mortality trends using joinpoint analysis. Kaplan-Meier analysis was performed for 5-, 10-, 15- and 20-year overall survival and cancer-specific survival rates. RESULTS: A total of 14,083PCa patients with a mean age of initial PCa diagnosis being 70.1 (SD 8.6) was registered. The standardized incidence rates (per 100,000) increased from 18.9 in 1990 to 74.7 in 2012, while the standardized prevalence rates (per 100,000) increased from 69.9 in 1990 to 437.6 in 2012. Standardized PCa mortality rates (per 100,000) also rose from 13.2 in 1990 to 27.2 in 2006 followed by statistically insignificant decrease continuing up to 2012. The mean 5-year cancer-specific survival rates increased from 43.6% in 1990 to 70.7% in 2007, and the mean 10-year cancer-specific survival rates from 32.9% in 1990 to 40.5% in 2001. CONCLUSIONS: This study revealed that the incidence, prevalence and mortality rates increased between 1990 and 2012, and although the 5- and 10-year overall and cancer-specific survival rates improved over the reviewed period they still needed to get better.

Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4-4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4-2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4-2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.

BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families.

BACKGROUND: The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group. METHODS: 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP. RESULTS: Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%. CONCLUSIONS: Molecular screening of sequential cancer patients is an important tool to identify HBOC families.

Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review.

BACKGROUND: While BRCA1/2 gene mutational spectrum and clinical features are widely studied, there is limited data on breast cancer-predisposing non-BRCA pathogenic/likely pathogenic variants (PV/LPVs) in the Baltic states region. According to previous studies, CHEK2 is the most frequent moderate-risk breast cancer predisposition gene. The study aimed to analyse the frequency and mutational spectrum of CHEK2 PV/LPVs in the Baltic states region and perform a literature review on the subject. METHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords 'CHEK2', 'breast cancer', 'Estonia', 'Lithuania', 'Latvia', 'Poland', 'Belarus' and 'Russia'. RESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus. CONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant's pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort.

BACKGROUND: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. METHODS: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. RESULTS: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. CONCLUSION: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.

Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia.

BACKGROUND: Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers. METHODS: We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers. RESULTS: We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1st and 2nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation. CONCLUSIONS: Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.

Epidemiologic, clinical, and molecular characteristics of hereditary prostate cancer in Latvia.

BACKGROUND AND OBJECTIVE: Prostate cancer is one of the most commonly diagnosed malignancy affecting men in Latvia. The aim of this study was to evaluate the epidemiological features and molecular basis of hereditary prostate cancer in Latvia. MATERIAL AND METHODS: A total of 1217 newly diagnosed prostate cancer patients were recruited in our study. Data were analyzed according to clinical diagnostic criteria for hereditary prostate cancer. Molecular testing for the founder mutation 657del5 of the NBS1 gene was performed for the first 280 prostate cancer patients and 173 control cases, and for the founder mutations 300T/G, 4153delA, and 5382insC of the BRCA1 gene for 112 prostate cancer patients with a history of breast or ovarian cancer in their families. RESULTS: Of the 1217 families, 14 (1.2%; 95% CI, 0.7%-1.9%) matched clinical diagnostic criteria for definitive hereditary prostate cancer, and of the 1217 families, 196 (16.1%; 95% CI, 14.1%-18.3%) for suspected hereditary prostate cancer. The founder mutation of the NBS1 gene was detected in 1 (0.4%, 95% CI, 0.1%-2.0%) of the 280 cases in the prostate cancer group and in 1 (0.6%; 95% CI, 0.1%-3.2%) of the 173 cases in the control group. The mutation 5382insC of the BRCA1 gene was detected in 2 (1.8%; 95% CI, 0.5%-6.3%) of the 112 cases analyzed in the prostate cancer group. No other BRCA1 founder mutations were detected. CONCLUSIONS: Our study did not reveal predisposition genes for hereditary prostate cancer as the founder mutations of the BRCA1 and NBS1 genes are rarely detected in Latvia, but showed the importance of evaluation risk individually as a positive family history of cancer was associated with the earlier onset of prostate cancer.

Blood Arsenic Levels as a Marker of Breast Cancer Risk among BRCA1 Carriers.

An important group of breast cancers is those associated with inherited susceptibility. In women, several predisposing mutations in genes involved in DNA repair have been discovered. Women with a germline pathogenic variant in BRCA1 have a lifetime cancer risk of 70%. As part of a larger prospective study on heavy metals, our aim was to investigate if blood arsenic levels are associated with breast cancer risk among women with inherited BRCA1 mutations. A total of 1084 participants with pathogenic variants in BRCA1 were enrolled in this study. Subjects were followed from 2011 to 2020 (mean follow-up time: 3.75 years). During that time, 90 cancers were diagnosed, including 67 breast and 10 ovarian cancers. The group was stratified into two categories (lower and higher blood As levels), divided at the median (<0.85 µg/L and ≥0.85 µg/L) As level among all unaffected participants. Cox proportional hazards models were used to model the association between As levels and cancer incidence. A high blood As level (≥0.85 µg/L) was associated with a significantly increased risk of developing breast cancer (HR = 2.05; 95%CI: 1.18-3.56; p = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09-2.74; p = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in BRCA1.

Initial results of colorectal polyposis research in Latvia.

AIM: Patients suffering from colorectal polyps are more likely to develop a malignant condition with poor prognosis. The aim of the study is to investigate clinical and molecular features of colorectal polyposis syndromes in Latvia in order to offer and provide predictive genetic testing for the affected families, as well as to evaluate the frequency of familial adenomatous polyposis (FAP) in Latvia. PATIENTS AND METHODS: Six polyposis patients along with three of their relatives were included in this study. Two patients were selected from the colorectal cancer database (from a total of 2,552), and four patients not affected with colorectal cancer (CRC) were referred from the endoscopic facility of our hospital. All the patients were examined during the period from January 1st, 2000 until June 30th, 2007. Clinical data, histological examinations and family cancer histories of the respective patients were evaluated. Screening for germline APC mutations was performed in five patients and their relatives. In addition, all patients underwent genetic counseling. RESULTS: Two patients out of 2,552 from the CRC Hereditary Cancer Institute database fulfilled the clinical criteria for FAP. Thus, the frequency of FAP is 0.08% (2/2,552) of all CRC cases, and comprises approximately 0.0003% of the population of Latvia (7/22 million inhabitants). Unknown polyposis was identified in two cases. Pathogenic APC gene mutations were detected in five out of seven examined patients and their relatives. Two of the mutations (c.3942delG:p.Arg1314SerfsX7 and c.3286C > T;p.Gln1096X) are novel. CONCLUSION: In this study, we report the first four APC mutation-positive FAP cases in Latvia. The present frequency of FAP is lower than that reported in Finland, Lithuania, and other neighbouring countries, but the numbers might increase if a more systematic identification approach is used. Initial molecular examinations reveal partially unique spectrum of APC gene mutations.