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RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer

SIMPLE SUMMARY: Breast cancer is the second leading cause of death in women. Identifying novel genetic factors conferring BC predisposition is crucial to predict who is at increased risk of developing the disease, allowing for early detection and therapy, and optimized patient management. We identif...

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Autores principales: Isidori, Federica, Bozzarelli, Isotta, Ferrari, Simona, Godino, Lea, Innella, Giovanni, Turchetti, Daniela, Bonora, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563829/
https://www.ncbi.nlm.nih.gov/pubmed/32906649
http://dx.doi.org/10.3390/cancers12092539
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author Isidori, Federica
Bozzarelli, Isotta
Ferrari, Simona
Godino, Lea
Innella, Giovanni
Turchetti, Daniela
Bonora, Elena
author_facet Isidori, Federica
Bozzarelli, Isotta
Ferrari, Simona
Godino, Lea
Innella, Giovanni
Turchetti, Daniela
Bonora, Elena
author_sort Isidori, Federica
collection PubMed
description SIMPLE SUMMARY: Breast cancer is the second leading cause of death in women. Identifying novel genetic factors conferring BC predisposition is crucial to predict who is at increased risk of developing the disease, allowing for early detection and therapy, and optimized patient management. We identified germline pathogenic variants in familial breast cancer patients in ROS1 and RASAL1 genes. Further analysis in independent patient group will help understanding the role of these novel genes in breast cancer predisposition. ABSTRACT: Breast cancer (BC) is the second leading cause of death in women. BC patients with family history or clinical features suggestive of inherited predisposition are candidate to genetic testing to determine whether a hereditary cancer syndrome is present. We aimed to identify new predisposing variants in familial BC patients using next-generation sequencing approaches. We performed whole exome sequencing (WES) in first-degree cousin pairs affected by hereditary BC negative at the BRCA1/2 (BReast CAncer gene 1/2) testing. Targeted analysis, for the genes resulting mutated via WES, was performed in additional 131 independent patients with a suspected hereditary predisposition (negative at the BRCA1/2 testing). We retrieved sequencing data for the mutated genes from WES of 197 Italian unrelated controls to perform a case-controls collapsing analysis. We found damaging variants in NPL (N-Acetylneuraminate Pyruvate Lyase), POLN (DNA Polymerase Nu), RASAL1 (RAS Protein Activator Like 1) and ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), shared by the corresponding cousin pairs. We demonstrated that the splice site alterations identified in NPL and ROS1 (in two different pairs, respectively) impaired the formation of the correct transcripts. Target analysis in additional patients identified novel and rare damaging variants in RASAL1 and ROS1, with a significant allele frequency increase in cases. Moreover, ROS1 achieved a significantly higher proportion of variants among cases in comparison to our internal control database of Italian subjects (p = 0.0401). Our findings indicate that germline variants in ROS1 and RASAL1 might confer susceptibility to BC.
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spelling pubmed-75638292020-10-27 RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer Isidori, Federica Bozzarelli, Isotta Ferrari, Simona Godino, Lea Innella, Giovanni Turchetti, Daniela Bonora, Elena Cancers (Basel) Article SIMPLE SUMMARY: Breast cancer is the second leading cause of death in women. Identifying novel genetic factors conferring BC predisposition is crucial to predict who is at increased risk of developing the disease, allowing for early detection and therapy, and optimized patient management. We identified germline pathogenic variants in familial breast cancer patients in ROS1 and RASAL1 genes. Further analysis in independent patient group will help understanding the role of these novel genes in breast cancer predisposition. ABSTRACT: Breast cancer (BC) is the second leading cause of death in women. BC patients with family history or clinical features suggestive of inherited predisposition are candidate to genetic testing to determine whether a hereditary cancer syndrome is present. We aimed to identify new predisposing variants in familial BC patients using next-generation sequencing approaches. We performed whole exome sequencing (WES) in first-degree cousin pairs affected by hereditary BC negative at the BRCA1/2 (BReast CAncer gene 1/2) testing. Targeted analysis, for the genes resulting mutated via WES, was performed in additional 131 independent patients with a suspected hereditary predisposition (negative at the BRCA1/2 testing). We retrieved sequencing data for the mutated genes from WES of 197 Italian unrelated controls to perform a case-controls collapsing analysis. We found damaging variants in NPL (N-Acetylneuraminate Pyruvate Lyase), POLN (DNA Polymerase Nu), RASAL1 (RAS Protein Activator Like 1) and ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), shared by the corresponding cousin pairs. We demonstrated that the splice site alterations identified in NPL and ROS1 (in two different pairs, respectively) impaired the formation of the correct transcripts. Target analysis in additional patients identified novel and rare damaging variants in RASAL1 and ROS1, with a significant allele frequency increase in cases. Moreover, ROS1 achieved a significantly higher proportion of variants among cases in comparison to our internal control database of Italian subjects (p = 0.0401). Our findings indicate that germline variants in ROS1 and RASAL1 might confer susceptibility to BC. MDPI 2020-09-07 /pmc/articles/PMC7563829/ /pubmed/32906649 http://dx.doi.org/10.3390/cancers12092539 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Isidori, Federica
Bozzarelli, Isotta
Ferrari, Simona
Godino, Lea
Innella, Giovanni
Turchetti, Daniela
Bonora, Elena
RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title_full RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title_fullStr RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title_full_unstemmed RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title_short RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
title_sort rasal1 and ros1 gene variants in hereditary breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563829/
https://www.ncbi.nlm.nih.gov/pubmed/32906649
http://dx.doi.org/10.3390/cancers12092539
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