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A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [CNV-seq]

ABSTRACT: The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSBs), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered sequence variants of uncertain clinical significance (VUS). Using genetically engineered mice, we now show that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupting the interaction with PALB2 leads to embryonic lethality and loss of breast cancer suppression. Brca1 p.L1363P mammary tumors develop with a similar latency as Brca1-null tumors, but show different histopathological features and more stable DNA copy number profiles. Nevertheless, Brca1 p.L1363P mammary tumors are HRR-incompetent and responsive to cisplatin and PARP inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE182449 | GEO | 2022/02/01

REPOSITORIES: GEO

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A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [RNA-seq]

Project description:The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSBs), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered sequence variants of uncertain clinical significance (VUS). Using genetically engineered mice, we now show that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupting the interaction with PALB2 leads to embryonic lethality and loss of breast cancer suppression. Brca1 p.L1363P mammary tumors develop with a similar latency as Brca1-null tumors, but show different histopathological features and more stable DNA copy number profiles. Nevertheless, Brca1 p.L1363P mammary tumors are HRR-incompetent and responsive to cisplatin and PARP inhibition.

2022-02-01 | GSE182448 | GEO

A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair.

Project description:A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair.

| PRJNA756277 | ENA

A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [RNA-seq]

Project description:A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [RNA-seq]

| PRJNA756281 | ENA

A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [CNV-seq]

Project description:A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [CNV-seq]

| PRJNA756282 | ENA

Expression data from HT-1080 cells incubated or not in the presence of laminin111 coiled-coiled recombinant fragment (rLCC111)

Project description:Laminins are large heterotrimeric cross-shaped extracellular matrix (ECM) glycoproteins with terminal globular domains and a coiled-coil region. We have produced for the first time a recombinant laminin coiled-coil domain and studied the transcriptional profile of cells incubated in coiled-coil-coated wells. Cells were incubated in 24w plates, onto coiled-coil-coated wells or control BSA-coated wells (one each), 24h

2011-10-11 | E-GEOD-32896 | biostudies-arrayexpress

Expression data from HT-1080 cells incubated or not in the presence of laminin111 coiled-coiled recombinant fragment (rLCC111)

2011-10-12 | GSE32896 | GEO

aCGH analysis of Palb2GT/+;p53-/- and Palb2+/+;p53-/- lymphomas

Project description:Palb2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair via homologous recombination. Heterozygous germline mutations in PALB2 confer a moderate risk of breast cancer while biallelic PALB2 mutations are linked to a severe form of Fanconi anaemia characterized by early childhood solid tumours and severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated cancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss of the wild type allele, suggesting PALB2 might be haploinsufficient for tumour suppression. To study the role of PALB2 in development and tumourigenesis, we have generated Palb2GT mouse mutants using a gene trap approach. Whereas Palb2GT/GT homozygous mutant embryos died at mid-gestation due to massive apoptosis, Palb2GT/+ heterozygous mice were viable and did not show any obvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2GT/GT embryos, but did not rescue embryonic lethality. In addition, loss of p53 did not significantly collaborate with Palb2 heterozygosity in tumourigenesis in heterozygous or homozygous p53 knockout mice. Tumours arising in Palb2GT/+;p53+/– or Palb2GT/+;p53–/– compound mutant mice retained the wild type Palb2 allele and did not display increased genomic instability. Comparison of 15 Palb2GT/+;p53-/- and 11 Palb2+/+;p53-/- lymphomas. Spleen/liver DNA of the same animal was used as reference material.

2011-01-21 | E-GEOD-26723 | biostudies-arrayexpress

aCGH analysis of Palb2GT/+;p53-/- and Palb2+/+;p53-/- lymphomas

2011-01-21 | GSE26723 | GEO

Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains

Project description:Delineating functionally normal variants from functionally abnormal variants in tumor suppressor proteins is critical for cancer surveillance, prognosis, and treatment options. BRCA1 is a protein that has many variants of uncertain significance which are not yet classified as functionally normal or abnormal. In vitro functional assays can be used to identify the functional impact of a variant when the variant has not yet been categorized through clinical observation. Here we employ a homology-directed repair (HDR) reporter assay to evaluate over 300 missense and nonsense BRCA1 variants between amino acid residues 1280 and 1576, which encompasses the coiled-coil and serine cluster domains. Functionally abnormal variants tended to cluster in residues known to interact with PALB2, which is critical for homology-directed repair. Multiplexed results were confirmed by singleton assay and by ClinVar database variant interpretations. Comparison of multiplexed results to designated benign or likely benign or pathogenic or likely pathogenic variants in the ClinVar database yielded 100% specificity and 100% sensitivity of the multiplexed assay. Clinicians can reference the results of this functional assay for help in guiding cancer treatment and surveillance options. These results are the first to evaluate this domain of BRCA1 using a multiplexed approach and indicate the importance of this domain in the DNA repair process.

2023-10-13 | GSE237142 | GEO

BRCAness and Merkel cell carcinoma: Comprehensive molecular study of 35 cases and meta-analysis of the literature

Project description:Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors (ICI). The high failure rate (up to 75%) warrants investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors (PARPi) in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a novel series of 35 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant (nonsense mutation; ENIGMA class 5) and one BRCA2 variant of unknown significance (VUS). The low frequency of BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants of the literature. Among the 204 MCC studied for molecular alterations of BRCA1/2, only two BRCA1 pathogenic nonsense mutations were identified (1%), while the vast majority of BRCA1/2 variants were missense mutations classified as VUS. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated-MCC, PARPi might be a valuable therapeutic option requiring validation by clinical trials.

2022-08-06 | GSE210602 | GEO

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