Purpose
To analyze the prevalence of pathogenic/likely pathogenic variants (P/LPVs) in
BRCA1
and
BRCA2
genes in the largest cohort of Slovenian male breast cancer (MBC) patients to date and to ...explore a possible correlation between the Slovenian founder variant
BRCA2
:c.7806-2A > G and predisposition to MBC.
Methods
We performed a retrospective analysis of 81 MBC cases who underwent genetic counseling and/or testing between January 1999 and May 2020. To explore a possible genotype–phenotype correlation, we performed additional analyses of 203 unrelated families with P/LPVs in
BRCA2
and 177 cases of female breast cancer (FBC) in carriers of P/LPVs in
BRCA2
.
Results
Detection rate of P/LPVs in the
BRCA1
and
BRCA2
genes was 24.7% (20/81) with 95% of them in
BRCA2
gene. The only two recurrent P/LPVs were
BRCA2
:c.7806-2A > G and
BRCA2
:c.3975_3978dupTGCT (9 and 5 MBC cases, respectively). In families with
BRCA2
:c.7806-2A > G, the incidence of MBC cases was higher compared to families with other P/LPVs in
BRCA2
; however, the difference did not reach statistical significance (17.8% vs. 8.9%,
p
= 0.105).
BRCA2
:c.7806-2A > G was detected in both families with multiple cases of MBC. This splice-site variant represented a significantly higher proportion of all
BRCA2
P/LPVs detected in MBC carriers compared to FBC carriers (47.4% vs. 26%,
p
= 0.049).
Conclusion
We observed a high mutation detection rate and conclude this may be due to the prevalent
BRCA2
:c.7806-2A > G variant in Slovenia. Our results indicate a possible association between this variant and higher risk of breast cancer in males compared to other identified P/LPVs in
BRCA2
.
Background
Currently, data on pathogenic variants in the
CHEK2
gene and their impact on cancer risk are lacking. This study aimed to explore the characteristics of breast cancer (BC) patients from ...families with
CHEK2
pathogenic variants in Slovenia.
Methods
In the years 2014 to 2019,
CHEK2
pathogenic variants/likely pathogenic variants (PV/LPVs) were found in probands from 50 different families who underwent genetic counseling and testing using a multigene panel at the authors’ institution. Altogether, the study enrolled 75 individuals from 50
CHEK2
families who were carriers of a
CHEK2
PV/LPV. The clinical data on 41 BC patients with
CHEK2
PV/LPV and other carriers of
CHEK2
PV/LPV from Slovenia were collected and analyzed.
Results
Breast cancer was diagnosed in 41 of 75
CHEK2
PV/LPV carriers (40 females, 1 male). The mean age at BC diagnosis was 42.8 years (range, 21–63 years), and 27 (65.8%) of the 41 of patients with BC had a positive family history for BC. Contralateral BC (CBC) was observed in 8 (19.5%) of the 41 patients (mean age, 55.6 years). Of 12 patients with human epidermal growth factor receptor 2 (HER2)-positive tumor type, a c.444+1G > A PV/LPV was detected in 4 patients, c.349A > G in 3 patients, deletion of exons 9–10 in 3 patients, deletion of exon 8 in 1 patient, and c.1427C > T PV/LPV in 1 patient.
Conclusion
Bilateral BC was diagnosed in as many as 19.5% of the Slovenian BC patients with
CHEK2
PV/LPVs. Breast cancer associated with a germline
CHEK2
PV/LPV occurs in younger patients compared with sporadic BC.
GOALSTo determine whether an 18 single nucleotide polymorphisms (SNPs) polygenic risk score (PRS18) improves breast cancer (BC) risk prediction for women at above-average risk of BC, aged 40-49, in a ...Central European population with BC incidence below EU average.METHODS502 women aged 40-49 years at the time of BC diagnosis completed a questionnaire on BC risk factors (as per Tyrer-Cuzick algorithm) with data known at age 40 and before BC diagnosis. Blood samples were collected for DNA isolation. 250 DNA samples from healthy women aged 50 served as a control cohort. 18 BC-associated SNPs were genotyped in both groups and PRS18 was calculated. The predictive power of PRS18 to detect BC was evaluated using a ROC curve. 10-year BC risk was calculated using the Tyrer-Cuzick algorithm adapted to the Slovenian incidence rate (S-IBIS): first based on questionnaire-based risk factors and, second, including PRS18.RESULTSThe AUC for PRS18 was 0.613 (95 % CI 0.570-0.657). 83.3 % of women were classified at above-average risk for BC with S-IBIS without PRS18 and 80.7 % when PRS18 was included.CONCLUSIONBC risk prediction models and SNPs panels should not be automatically used in clinical practice in different populations without prior population-based validation. In our population the addition of an 18SNPs PRS to questionnaire-based risk factors in the Tyrer-Cuzick algorithm in general did not improve BC risk stratification, however, some improvements were observed at higher BC risk scores and could be valuable in distinguishing women at intermediate and high risk of BC.
Background: Medullary thyroid cancer (MTC) is a rare endocrine tumour that is sporadic in 75% of cases and occurs as a part of inherited cancer syndromes in approximately 25% of cases. The aim of ...this study was to determine the frequency and type of RET pathogenic variants (PVs) in the Slovenian MTC patient population diagnosed between 1995 and 2021 and to elucidate the full range of associated endocrinopathies. Methods: A retrospective analysis of medical records of 266 MTC patients and their relatives seen in a tertiary centre between 1995 and 2021 was performed. Sequence analysis of exons 10, 11, 13, 14, 15, and 16 of the RET gene was analysed in most patients using Sanger sequencing. From 2017, the entire sequence of RET gene was analysed in most patients using targeted next-generation sequencing. Results: Germline PVs in the RET proto-oncogene were identified in 21.6% probands from 21 different MTC families. Of their tested relatives, 65% (67/103) were RET-positive and 35% (36/103) were RET-negative. PVs were detected in codon 618 and codon 634 in 28.6%, and in codon 790 in 23.8%. The RET-positive group consisted of 52 MTC patients, 13 patients with C cell hyperplasia and 2 individuals with neither. Associated endocrinopathies were diagnosed in 8/21 families: primary hyperparathyroidism (PHPT) in six families and pheochromocytoma (PHEO) in five families. In 62% of RET-positive families (13/21), no associated endocrinopathies were diagnosed. PHEO was most commonly associated with C634R (6/13) and PHPT with C634R (4/7). Hirschsprung’s disease appeared in one patient with RET PV in codon 618. Based on data from the Cancer Registry of Republic of Slovenia, only individual cases of common cancers with well understood environmental risk factors were discovered; lung cancer in 2/21 of families, papillary thyroid cancer in 3/21 of families, cutaneous melanoma in 2/21 of families, cervical cancer in 1/21 families, and lymphoma in 1/21 families. Conclusions: Analysis of prospectively collected MTC cases during a 27-year period revealed that 21.6% of Slovenian patients are RET PV carriers. Sixty-two percent of families had none of the associated endocrinopathies, confirming the thesis that FMTC is the most common presentation. This could suggest using risk-stratified management approaches when screening for PHEO and PHPT in RET PV carriers. However, more studies are needed to evaluate potential genetic risk modifiers as well as safety, improved quality of life, and medical cost reduction in the case of a patient-oriented approach.
High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation ...are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples.
Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared.
Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples.
There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients.
The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .
The organised, population-based breast cancer screening programme in Slovenia began providing biennial mammography screening for women aged 50-69 in 2008. The programme has taken a comprehensive ...approach to quality assurance as recommended by the European guidelines for quality assurance in breast cancer screening and diagnosis (4th edition), including centralized assessment, training and supervision, and proactive monitoring of performance indicators. This report describes the progress of implementation and rollout from 2003 through 2019. The screening protocol and key quality assurance procedures initiated during the planning from 2003 and rollout from 2008 of the screening programme, including training of the professional staff, are described. The organisational structure, gradual geographical rollout, and coverage by invitation and examination are presented. The nationwide programme was up and running in all screening regions by the end of 2017, at which time the nationwide coverage by invitation and examination had reached 70% and 50%, respectively. Nationwide rollout of the population-based programme was complete by the end of 2019. By this time, coverage by invitation and examination had reached 98% and 76%, respectively. The participation rates consistently exceeded 70% from 2014 to 2019. The successful implementation of the screening programme can be attributed to an independent central management, external guidance, and strict adherence to quality assurance procedures, all of which contributed to increasing governmental and popular support. The benefits of quality assurance have influenced all aspects of breast care and have provided a successful model for multidisciplinary management of other diseases.
Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not ...performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.
Abstract Background The evidence shows that risk-based strategy could be implemented to avoid unnecessary harm in mammography screening for breast cancer (BC) using age-only criterium. Our study ...aimed at identifying the uptake of Slovenian women to the BC risk assessment invitation and assessing the number of screening mammographies in case of risk-based screening. Patients and methods A cross-sectional population-based study enrolled 11,898 women at the age of 50, invited to BC screening. The data on BC risk factors, including breast density from the first 3,491 study responders was collected and BC risk was assessed using the Tyrer-Cuzick algorithm (version 8) to classify women into risk groups (low, population, moderately increased, and high risk group). The number of screening mammographies according to risk stratification was simulated. Results 57% (6,785) of women returned BC risk questionnaires. When stratifying 3,491 women into risk groups, 34.0% were assessed with low, 62.2% with population, 3.4% with moderately increased, and 0.4% with high 10-year BC risk. In the case of potential personalised screening, the number of screening mammographies would drop by 38.6% compared to the current screening policy. Conclusions The study uptake showed the feasibility of risk assessment when inviting women to regular BC screening. 3.8% of Slovenian women were recognised with higher than population 10-year BC risk. According to Slovenian BC guidelines they may be screened more often. Overall, personalised screening would decrease the number of screening mammographies in Slovenia. This information is to be considered when planning the pilot and assessing the feasibility of implementing population risk-based screening.
Abstract Background The aim of the study was to assess the proportion of women that would be classified as at above-average risk of breast cancer based on the 10 year-risk prediction of the Slovenian ...breast cancer incidence rate (S-IBIS) program in two presumably above-average breast cancer risk populations in age group 40-49 years: (i) women referred for any reason to diagnostic breast centres and (ii) women who were diagnosed with breast cancer aged 40–49 years. Breast cancer is the commonest female cancer in Slovenia, with an incidence rate below European average. The Tyrer-Cuzick breast cancer risk assessment algorithm was recently adapted to S-IBIS. In Slovenia a tailored mammographic screening for women at above average risk in age group 40–49 years is considered in the future. S-IBIS is a possible tool to select population at above-average risk of breast cancer for tailored screening. Patients and methods In 357 healthy women aged 40–49 years referred for any reason to diagnostic breast centres and in 367 female breast cancer patients aged 40–49 years at time of diagnosis 10-years breast cancer risk was calculated using the S-IBIS software. The proportion of women classified as above-average risk of breast cancer was calculated for each subgroup of the study population. Results 48.7% of women in the Breast centre group and 39.2% of patients in the breast cancer group had above-average 10-year breast cancer risk. Positive family history of breast cancer was more prevalent in the Breast centre group (p < 0.05). Conclusions Inclusion of additional risk factors into the S-IBIS is warranted in the populations with breast cancer incidence below European average to reliably stratify women into breast cancer risk groups.
Background We assessed the incidence and characteristics of interval cancers after faecal immunochemical occult blood test and calculated the test sensitivity in Slovenian colorectal cancer screening ...programme. Patients and methods The analysis included the population aged between 50 to 69 years, which was invited for screening between April 2011 and December 2012. The persons were followed-up until the next foreseen invitation, in average for 2 years. The data on interval cancers and cancers in non-responders were obtained from cancer registry. Gender, age, years of schooling, the cancer site and stage were compared among three observed groups. We used the proportional incidence method to calculate the screening test sensitivity. Results Among 502,488 persons invited for screening, 493 cancers were detected after positive screening test, 79 interval cancers after negative faecal immunochemical test and 395 in non-responders. The proportion of interval cancers was 13.8%. Among the three observed groups cancers were more frequent in men (p = 0.009) and in persons aged 60+ years (p < 0.001). Comparing screen detected and cancers in non-responders with interval cancers more interval cancers were detected in persons with 10 years of schooling or more (p = 0.029 and p = 0.001), in stage III (p = 0.027) and IV (p < 0.001), and in right hemicolon (p < 0.001). Interval cancers were more frequently in stage I than non-responders cancers (p = 0.004). Test sensitivity of faecal immunochemical test was 88.45%. Conclusions Interval cancers in Slovenian screening programme were detected in expected proportions as in similar programmes. Test sensitivity was among the highest when compared to similar programmes and was accomplished using test kit for two stool samples.
PDF
