The Role of PALB2 in the DNA Damage Response and Cancer Predisposition

Nepomuceno, Thales C.; Gregoriis, Giuliana De; Oliveira, Francisco Meirelles Bastos de; Suarez‐Kurtz, Guilherme; Monteiro, Alvaro N.A.; Carvalho, Marcelo A.

doi:10.3390/ijms18091886

Cited by 76 publications

(75 citation statements)

References 153 publications

(225 reference statements)

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“…So, the mutations in PALB2 normally not only resulted in typical FA phenotypes, but also increased the occurrence of pediatric malignancies, Wilm's tumors, and medulloblastomas (Reid et al, 2007). Importantly, the cancer spectrum caused by mutations in PALB2 is quite similar to that induced by mutations in BRCA2, thereby validating the direct interaction between PALB2 and BRCA2 (Nepomuceno et al, 2017).…”

Section: Palb2/fancnmentioning

confidence: 83%

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Fang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.

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Section: Palb2/fancnmentioning

confidence: 83%

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Fang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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“…PALB2 loss-offunction mutations are associated with sensitivity to DNA-damaging agents and poly(ADP-ribose) polymerase 1 inhibitors. 11 To the best of our knowledge, this is the first study to explore PALB2 mRNA expression as a predictive pharmacogenomic marker in NSCLC. We found that PALB2, when highly expressed, is predictive of outcome in response to cisplatin-docetaxel.…”

Section: Discussionmentioning

confidence: 94%

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer

Karachaliou

Bracht

Bruno

et al. 2019

Journal of Thoracic Oncology

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Introduction: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). Methods:The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatindocetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response.Results: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio ¼ 0.63, 95% confidence interval: 0.42-0.83, p ¼ 0.0080). PALB2 was also predictive of overall survival (hazard ratio ¼ 0.68, 95% confidence interval: 0.42-0.90, p ¼ 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive

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“…PALB2 is located in the 16p chromosome arm and encodes a putative tumor suppressor protein that interacts with BRCA2 through dimerization and the recombinase RAD51. It plays a role in DNA repair by acting in the Fanconi anemia and homologous recombination pathways . PALB2 germline mutations predispose to breast and pancreatic cancers , and its promoter may also be silenced by DNA methylation .…”

Section: Discussionmentioning

confidence: 99%

“…It plays a role in DNA repair by acting in the Fanconi anemia and homologous recombination pathways . PALB2 germline mutations predispose to breast and pancreatic cancers , and its promoter may also be silenced by DNA methylation . PALB2 alterations appear to be rare in glioma with only a single homozygous inactivation of this gene reported among 794 diffuse gliomas in the TCGA dataset (http://www.cbioportal.org).…”

Section: Discussionmentioning

confidence: 99%

Granular cell astrocytoma: an aggressive IDH‐wildtype diffuse glioma with molecular genetic features of primary glioblastoma

et al. 2018

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Granular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA-1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), -13q in 4 of 6, and -14 in 4 of 6. Next-generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB-1 (P > 0.05). GCA is a variant of IDH-wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.

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The Role of PALB2 in the DNA Damage Response and Cancer Predisposition

Cited by 76 publications

References 153 publications

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer

Granular cell astrocytoma: an aggressive IDH‐wildtype diffuse glioma with molecular genetic features of primary glioblastoma

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