Dataset Information

Double Heterozygosity for BRCA1 Pathogenic Variant and BRCA2 Polymorphic Stop Codon K3326X: A Case Report in a Southern Italian Family.

ABSTRACT: Here, we describe a patient with bilateral breast cancer and melanoma, and with a concomitant double variant, namely p.Gln563Ter in BRCA1 and p.Lys3326Ter in BRCA2. The BRCA2 p.Lys3326Ter (K3326X) (rs11571833) mutation identified in our patient is a debated substitution of thymidine for adenine which is currently regarded as benign polymorphism in main gene databases. Recent studies, however, describe this variant as associated with breast and ovarian tumors. Based on the observation of the cancer's earliest age of onset in this subject, our purpose was to reevaluate this variant according to recent papers indicating a role of powerful modifier of the genetic penetrance. Genetic testing was performed in all consenting patient's relatives, and in the collection of the clinical data particular attention was paid to the age of onset of the neoplasia. Following our observation that the our patient with double heterozygosis had an early age of onset for cancer similar to a few rare cases of double mutation for BRCA1 and BRCA2, we also performed an extensive review of the literature relative to patients carrying a double heterozygosity for both genes. In line with previous studies relative to the rare double heterozygosity in both BRCA1/2 genes, we found the earlier onset of breast cancer in our patient with both BRCA1/2 mutations with respect to other relatives carrying the single BRCA1 mutation. The presence of the second K3326X variant in our case induces a phenotype characterized by early onset of the neoplasia in a manner similar to the other cases of double heterozygosity previously described. Therefore, we suggest that during the genetic counseling, it should be recommendable to evaluate the presence of the K3326X variant in association with other pathogenic mutations.

SUBMITTER: Palmirotta R

PROVIDER: S-EPMC5796231 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Double Heterozygosity for BRCA1 Pathogenic Variant and BRCA2 Polymorphic Stop Codon K3326X: A Case Report in a Southern Italian Family.

Palmirotta Raffaele R Lovero Domenica D Stucci Luigia Stefania LS Silvestris Erica E Quaresmini Davide D Cardascia Angela A Silvestris Franco F

International journal of molecular sciences 20180118 1

Here, we describe a patient with bilateral breast cancer and melanoma, and with a concomitant double variant, namely p.Gln563Ter in BRCA1 and p.Lys3326Ter in BRCA2. The BRCA2 p.Lys3326Ter (K3326X) (rs11571833) mutation identified in our patient is a debated substitution of thymidine for adenine which is currently regarded as benign polymorphism in main gene databases. Recent studies, however, describe this variant as associated with breast and ovarian tumors. Based on the ob ...[more]

PMID: 29346284

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Project description:Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from non-carriers based on differences in expression profiling. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers. We identified 137 probe sets in BRCA1 carriers and 1345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell cycle regulation and apoptosis. Real-time PCR was performed on the 36 genes which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 or BRCA2 mutation carriers as compared to controls (p<0.05). Based on a validation study with 40 mutation carriers and 17 non-carriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed in order to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biological effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation induced DNA damage. We also suggest a set of 18 genes that can be used as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers Fresh blood samples were obtained from 9 BRCA1 and 8 BRCA2 mutation carriers and 9 mutation-negative women. Lymphocytes were collected from fresh blood samples, and RNA was extracted one hour after γ-irradiation

Dataset Information

Double Heterozygosity for BRCA1 Pathogenic Variant and BRCA2 Polymorphic Stop Codon K3326X: A Case Report in a Southern Italian Family.

Publications

Double Heterozygosity for BRCA1 Pathogenic Variant and BRCA2 Polymorphic Stop Codon K3326X: A Case Report in a Southern Italian Family.

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