Operable triple-negative breast cancer (TNBC) is an unfavorable subtype of breast cancer, which usually requires an aggressive perioperative systemic treatment. When TNBC presents as a second primary ...cancer after cured acute leukemia, its management might be challenging.
We present a case report of a young postmenopausal woman with an operable TNBC who had a history of the B-cell acute lymphoblastic leukemia (B-ALL) and graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). A history of previous treatment with anthracyclines and radiotherapy and GVHD limited the use of doxorubicin for treatment of her TNBC. Due to the history of GVHD, perioperative treatment with pembrolizumab was omitted. Genetic testing was challenging due to the possible contamination of her tissues with the donor's cells after allo-SCT. In samples of our patient's buccal swab, peripheral blood, and tumor tissue, a pathogenic variant in the partner and localizer of
(
) gene was found. With neoadjuvant chemotherapy which included carboplatin, a pathologic complete response was achieved. Although our patient has a low risk for recurrence of TNBC, her risk for the development of new primary cancers remains substantial.
This case highlights challenges in the systemic treatment, genetic testing, and follow-up of patients with operable TNBC and other solid cancers who have a history of acute leukemia.
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
.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Genome-wide sequencing approaches are increasingly being used in place of disease gene panel sequencing approaches. Despite the well-recognized benefits of these approaches, they also carry with them ...an increased burden of analyzing overwhelmingly large gene targets and an increased possibility of detecting incidental findings.
We propose a novel approach for design of individualized phenotype gene panels using the set of signs and symptoms observed and selecting relevant genes on the basis of known phenotype–gene associations.
We used results of diagnostic exome sequencing in 405 cases submitted to our institution to show retrospectively that using the phenotype gene panel increases the sensitivity of masked exome analysis (increase from 25.4 to 29.7% in overall diagnostic yield). We also show that such a strategy enables the possibility of masked analysis of genome-wide sequencing data in patients with poorly defined and multifaceted clinical presentations. Ultimately, we show that this approach enables control over the incidental findings rate (0.25% in phenotype gene panels). Finally, we provide a Web tool for customized phenotype panel creation (available at http://www.kimg.eu/generator).
In conclusion, we present a novel approach to a phenotype-driven diagnostic process of genome scale sequencing data that harnesses the sensitivity of these approaches while restricting the analysis to genes relevant to clinical presentation in patient.
Genet Med18 11, 1102–1110.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
Bilateral parotid gland aplasia is a rare congenital anomaly that almost consistently leads to xerostomia and caries. It is often associated with other congenital craniofacial ...abnormalities. The objective was to describe a case with asymptomatic bilateral parotid gland aplasia and to review previously reported cases.
Methods
Panoramic radiograph, computed tomography and magnetic resonance imaging were obtained and an in-depth assessment of patient’s dental status and sequence analysis of
FGF10, FGFR2
and
FGFR3
genes were performed. Previous reports of bilateral parotid gland aplasia were assessed.
Results
In a 64-year-old woman with extensive basal cell carcinoma of nasal skin an incidental bilateral parotid gland aplasia was noted during radiotherapy treatment planning. Dental status revealed surprisingly numerous (
n
= 15) teeth without active caries lesions. No other craniofacial abnormalities were identified. To rule out most probable syndromes associated with parotid gland aplasia, sequence analysis of
FGF10
,
FGFR2
and
FGFR3
genes was performed showing no pathogenic variants. With a literature review, we identified 148 cases of salivary gland aplasia in which median age at diagnosis was 21 years and one third were asymptomatic. In only 10 of these cases, the patients presented with bilateral aplasia of parotid glands without other craniofacial abnormalities.
Conclusions
Absence of salivary glands can have a debilitating effect on oral health and is often accompanied by other craniofacial abnormalities. However, relatively frequent asymptomatic course suggests that this rare malformation is probably underdiagnosed. Therefore, we propose systematic reporting of salivary gland aplasia to assess its true prevalence in general population.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neurofibromatosis type I (NF1) is one of the most common autosomal dominant disorders, since the estimated incidence is one in 3,500 births. In this study, we present bioinformatical and functional ...characterization of two novel splicing
variants, detected in NF1 patients. Patient 1, carrying
:c.122A>T, which introduces a new exonic 5' donor splice site, was diagnosed with hormone-positive, Her-2-negative breast cancer at the age of 47. She had an atypical presentation of NF1, with few café-au-lait spots and no Lisch nodules. Patient developed a hemothorax due to subclavian artery rupture, which has previously been described as an extremely rare complication of NF1. Patient 2, carrying
:c.7395-17T>G that creates a new intronic 3' acceptor splice site, had quite a typical clinical presentation of NF1: formations on her tongue in the region of her left metacarpal bones and on her left foot, plexiform neurofibroma in her pelvis, several café-au-lait spots, and axillary freckling. She was also diagnosed with cognitive impairment. In the report, we are presenting two novel variants which were successfully classified based on NGS and mRNA analysis. Based on results of mRNA analysis, both variants were classified as likely pathogenic according to ACMG guidelines applying evidence categories PS3, PM2, PP3, and PP1 supporting. By characterizing those two novel
splicing variants, we have confirmed the neurofibromatosis type I phenotype in the two probands.
Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary ...melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) ...using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel
in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in
. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel
variant as likely pathogenic, we confirmed the LS in this family.
PDF
