Dataset Information

Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development.

ABSTRACT: Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.

SUBMITTER: Huo Y

PROVIDER: S-EPMC8065161 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development.

Huo Yanying Y Selenica Pier P Mahdi Amar H AH Pareja Fresia F Kyker-Snowman Kelly K Chen Ying Y Kumar Rahul R Da Cruz Paula Arnaud A Basili Thais T Brown David N DN Pei Xin X Riaz Nadeem N Tan Yongmei Y Huang Yu-Xiu YX Li Tao T Barnard Nicola J NJ Reis-Filho Jorge S JS Weigelt Britta B Xia Bing B

NPJ breast cancer 20210423 1

Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ...[more]

PMID: 33893322

Similar Datasets

Project description:ObjectiveThe aim of this study was to determine the frequency of germline variants in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 in patients admitted to a medical genetics clinic with breast cancer and to assess these identified variants according to published genetic, surgical and oncological perspectives.Materials and methodsMedical history, and cancer diagnosis information for 195 independent probands with operated breast cancer were collected from requisition forms and medical records. The exonic regions and exon-intron junctions in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 genes were sequenced. Analysis of fastq files was performed on the Qiagen Clinical Insight-Analyse Universal with panel-specific pipeline and vcf files were interpreted clinically using Qiagen Clinical Insight-Interpret.ResultsGene variants (pathogenic, likely pathogenic and variants of unknown significance) were detected in 53 (27.2%). Detailed information about the patients (age of diagnosis, family history, gender), cancer stage, tumour characteristics (ER, PR, human epidermal growth factor receptor 2 status) and all information related to the detected variants (gene, location, nucleotide and amino acid change, exon number, impact, mutation classification, dbSNP number and HGMD variant class) were assessed. In total, 58 mutations were identified including 14 novel, previously unreported variants.ConclusionMolecular characterization and identification of mutations have important implications for predictive, preventive, and personalized medicine, including genetic counseling and development of specific treatment protocols. We emphasize variants of unknown significance (VUS) as the clinical significance of VUS changes over time and variant classification is important for clinical molecular genetic testing and clinical guidance. This study may provide new insights into risk assessment for variants in CDH1, PALB2, PTEN and TP53, in addition to BRCA1 and BRCA2, which may prove useful for clinical management of breast cancer patients. Further studies are needed to identify the common gene variants in the Turkish population and evaluate the pathogenity of VUS.

Dataset Information

Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development.

Publications

Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets