The aim of this report is to describe results of BRCA1 and BRCA2 Next Generation Sequencing Analysis (NGS) analysis in 132 selected Italian patients with breast/ovarian cancer. A NGS pipeline with a reliable Copy Number Variation (CNV) prediction algorithm was applied. In addition, VarSome and Priors V2.0 Software were employed for in silico analysis of novel missense variants. A total of 37 BRCA1 and BRCA2 pathogenic variants were found in 34 unrelated subjects with a frequency of positive patients of 25.7% (34/132). Twenty-four deleterious variants were detected in BRCA1 (representing the 64.9% of all identified pathogenic defects) and thirteen (35.1% of all identified pathogenic variants) in BRCA2 gene. The percentage of patients carrying a variant of unknown significance (VUS) was 7.5% (10/132). In addition, seven novel variants (five in BRCA2 and two in BRCA1 gene), never previously reported, were identified. Our approach represents a robust and easy-to-use method for full BRCA1/2 screening. However, a consistent number of our high-risk families still remained without a satisfying answer. Necessarily, further collective efforts must be directed to a definitive classification of VUSs. The future auspice is that the use of multi-gene panel and more advanced screenings, such as whole exome sequencing and/or RNA seq, in routine diagnostics increases the detection rate.
Lo scopo di questa relazione è descrivere i risultati dell'analisi di sequenziamento di nuova generazione (NGS) di BRCA1 e BRCA2 in 132 pazienti italiane selezionate con cancro al seno/ovarico. È stata applicata una pipeline NGS con un algoritmo affidabile di predizione delle variazioni del numero di copie (CNV). Inoltre, sono stati utilizzati i software VarSome e Priors V2.0 per l'analisi in silico di nuove varianti missenso. In totale sono state trovate 37 varianti patogene di BRCA1 e BRCA2 in 34 soggetti non imparentati, con una frequenza di pazienti positivi del 25,7% (34/132). Sono state individuate 24 varianti deleterie nel gene BRCA1 (che rappresentano il 64,9% di tutti i difetti patogeni identificati) e 13 (35,1% di tutte le varianti patogene identificate) nel gene BRCA2. La percentuale di pazienti portatori di una variante di significato sconosciuto (VUS) è stata del 7,5% (10/132). Inoltre, sono state identificate sette nuove varianti (cinque nel gene BRCA2 e due nel gene BRCA1), mai segnalate in precedenza. Il nostro approccio rappresenta un metodo robusto e facile da usare per lo screening completo di BRCA1/2. Tuttavia, un numero consistente di famiglie ad alto rischio è rimasto senza una risposta soddisfacente. Necessariamente, ulteriori sforzi collettivi devono essere indirizzati a una classificazione definitiva delle VUS. L'auspicio futuro è che l'uso di pannelli multi-gene e di screening più avanzati, come il sequenziamento dell'intero esoma e/o l'RNA seq, nella diagnostica di routine aumenti il tasso di individuazione.
SEQUENZIAMENTO DI NUOVA GENERAZIONE NEI GENI BRCA1 E BRCA2 RESPONSABILI DELLA PREDISPOSIZIONE GENETICA AL CANCRO
PASQUALI, CATERINA
2023/2024
Abstract
The aim of this report is to describe results of BRCA1 and BRCA2 Next Generation Sequencing Analysis (NGS) analysis in 132 selected Italian patients with breast/ovarian cancer. A NGS pipeline with a reliable Copy Number Variation (CNV) prediction algorithm was applied. In addition, VarSome and Priors V2.0 Software were employed for in silico analysis of novel missense variants. A total of 37 BRCA1 and BRCA2 pathogenic variants were found in 34 unrelated subjects with a frequency of positive patients of 25.7% (34/132). Twenty-four deleterious variants were detected in BRCA1 (representing the 64.9% of all identified pathogenic defects) and thirteen (35.1% of all identified pathogenic variants) in BRCA2 gene. The percentage of patients carrying a variant of unknown significance (VUS) was 7.5% (10/132). In addition, seven novel variants (five in BRCA2 and two in BRCA1 gene), never previously reported, were identified. Our approach represents a robust and easy-to-use method for full BRCA1/2 screening. However, a consistent number of our high-risk families still remained without a satisfying answer. Necessarily, further collective efforts must be directed to a definitive classification of VUSs. The future auspice is that the use of multi-gene panel and more advanced screenings, such as whole exome sequencing and/or RNA seq, in routine diagnostics increases the detection rate.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12075/18199