Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Boonen, Rick A.C.M.; Vreeswijk, Maaike P.G.; Attikum, Haico van

doi:10.3389/fmolb.2020.00169

Cited by 11 publications

(10 citation statements)

References 111 publications

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“…Complementation by transient overexpression of PALB2 cDNA carrying this variant, versus complementation by stable integration, may explain this difference as discussed previously. 28 Our data are generally in agreement with previous studies showing that p.R37H exhibits a moderate impact on HR, although HR rates are slightly variable between the different studies. [14][15][16][17] An impaired PALB2-BRCA1 interaction likely explains this defect, as well as the reduced recruitment of p.R37H to sites of DNA damage induced by laser micro-irradiation.…”

Section: Functional Characterisation Of Palb2 Rare Missense Variantssupporting

confidence: 93%

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Boonen

Wijaya

et al. 2021

J Med Genet

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BackgroundRare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.MethodsMutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.ResultsPTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.ConclusionDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

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Section: Functional Characterisation Of Palb2 Rare Missense Variantssupporting

confidence: 93%

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Boonen

Wijaya

et al. 2021

J Med Genet

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“…Moderate but statistically significant (P < 0.0001) PARPi sensitivity was observed (76% cell survival), whereas wild type PALB2 had 100% cell survival 55 . The homology-directed repair assay found p.(P8L) to have an intermediate phenotype with a 40% reduction in HR when compared to wild type PALB2 55 , 56 , all of which appear to indicate that this variant may play a role in breast cancer.…”

Section: Discussionmentioning

confidence: 94%

Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients of African ancestry

Eygelaar

Rensburg

Joubert

2022

Sci Rep

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Since the discovery of the breast cancer susceptibility genes, BRCA1 and BRCA2, various other genes conferring an increased risk for breast cancer have been identified. Studies to evaluate sequence variants in cancer predisposition genes among women of African ancestry are limited and mostly focused on BRCA1 and BRCA2. To characterize germline sequence variants in cancer susceptibility genes, we analysed a cohort of 165 South African women of self-identified African ancestry diagnosed with breast cancer, who were unselected for family history of cancer. With the exception of four cases, all others were previously investigated for BRCA1 and BRCA2 deleterious variants, and were negative for pathogenic variants. We utilized the Illumina TruSight cancer panel for targeted sequencing of 94 cancer susceptibility genes. A total of 3.6% of patients carried a pathogenic/likely pathogenic variant in a known breast cancer susceptibility gene: 1.2% in BRCA1, 0.6% in each of BRCA2, ATM, CHEK2 and PALB, none of whom had any family history of breast cancer. The mean age of patients who carried deleterious variant in BRCA1/BRCA2 was 39 years and 8 months compared to 47 years and 3 months among women who carried a deleterious variant in other breast cancer susceptibility genes.

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“…The development of a platform for the functional characterization of VUS has been shown very successfully in the field of oncology, particularly breast cancers associated with mutations in BRCA genes, leading to a significant improvement in the clinical management of cancer patients ( Guidugli et al, 2014 ; Woods et al, 2016 ; Federici and Soddu, 2020 ). Another example is the different pathogenic variants in the gene PALB2 associated with varying levels of risk for breast, ovarian and pancreatic cancers ( Boonen et al, 2020 ). Using a combination of complementary in vitro assays, researchers can assess the impact of specific PALB2 VUS, at the level of individual patients, on the function of the protein in DNA repair, cell cycle regulation and the control of cellular levels of reactive oxygen species ( Boonen et al, 2020 ).…”

Section: Using Zebrafish To Predict Neurological Disease Susceptibili...mentioning

confidence: 99%

“…Another example is the different pathogenic variants in the gene PALB2 associated with varying levels of risk for breast, ovarian and pancreatic cancers ( Boonen et al, 2020 ). Using a combination of complementary in vitro assays, researchers can assess the impact of specific PALB2 VUS, at the level of individual patients, on the function of the protein in DNA repair, cell cycle regulation and the control of cellular levels of reactive oxygen species ( Boonen et al, 2020 ). This functional characterization of VUS can be valuable for predicting cancer risk and anticipating treatment-responsiveness to cancer therapy for each patient.…”

Section: Using Zebrafish To Predict Neurological Disease Susceptibili...mentioning

confidence: 99%

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

Ochenkowska

Herold

Samarut

2022

Front. Mol. Neurosci.

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Personalized medicine is currently one of the most promising tools which give hope to patients with no suitable or no available treatment. Patient-specific approaches are particularly needed for common diseases with a broad phenotypic spectrum as well as for rare and yet-undiagnosed disorders. In both cases, there is a need to understand the underlying mechanisms and how to counteract them. Even though, during recent years, we have been observing the blossom of novel therapeutic techniques, there is still a gap to fill between bench and bedside in a patient-specific fashion. In particular, the complexity of genotype-to-phenotype correlations in the context of neurological disorders has dampened the development of successful disease-modifying therapeutics. Animal modeling of human diseases is instrumental in the development of therapies. Currently, zebrafish has emerged as a powerful and convenient model organism for modeling and investigating various neurological disorders. This model has been broadly described as a valuable tool for understanding developmental processes and disease mechanisms, behavioral studies, toxicity, and drug screening. The translatability of findings obtained from zebrafish studies and the broad prospect of human disease modeling paves the way for developing tailored therapeutic strategies. In this review, we will discuss the predictive power of zebrafish in the discovery of novel, precise therapeutic approaches in neurosciences. We will shed light on the advantages and abilities of this in vivo model to develop tailored medicinal strategies. We will also investigate the newest accomplishments and current challenges in the field and future perspectives.

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Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Cited by 11 publications

References 111 publications

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients of African ancestry

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

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