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      A novel germline PALB2 deletion in Polish breast and ovarian cancer patients

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          Abstract

          Background

          PALB2 protein was recently identified as a partner of BRCA1 and BRCA2 which determines their proper function in DNA repair.

          Methods

          Initially, the entire coding sequence of the PALB2 gene with exon/intron boundaries was evaluated by the PCR-SSCP and direct sequencing methods on 70 ovarian carcinomas. Sequence variants of interest were further studied on enlarged groups of ovarian carcinomas (total 339 non-consecutive ovarian carcinomas), blood samples from 334 consecutive sporadic and 648 consecutive familial breast cancer patients, and 1310 healthy controls from central Poland.

          Results

          Ten types of sequence variants were detected, and among them four novel polymorphisms: c.2996+58T>C in intron 9; c.505C>A (p.L169I), c.618T>G (p.L206L), both in exon 4; and c.2135C>T (A712V) in exon 5 of the PALB2 gene. Another two polymorphisms, c.212-58A>C and c.2014G>C (E672Q) were always detected together, both in cancer (7.5% of patients) and control samples (4.9% of controls, p = 0.2). A novel germline truncating mutation, c.509_510delGA (p.R170fs) was found in exon 4: in 2 of 339 (0.6%) unrelated ovarian cancer patients, in 4 of 648 (0.6%) unrelated familial breast cancer patients, and in 1 of 1310 controls (0.08%, p = 0.1, p = 0.044, respectively). One ovarian cancer patient with the PALB2 mutation had also a germline nonsense mutation of the BRCA2 gene.

          Conclusions

          The c.509_510delGA is a novel PALB2 mutation that increases the risk of familial breast cancer. Occurrence of the same PALB2 alteration in seven unrelated women suggests that c.509_510delGA (p.R170fs) is a recurrent mutation for Polish population.

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          Most cited references19

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          Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.

          BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.
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            Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.

            Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.
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              PALB2 links BRCA1 and BRCA2 in the DNA-damage response.

              BRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of PALB2 by small interfering RNA. Moreover, we show that BRCA1 promotes the concentration of PALB2 and BRCA2 at DNA-damage sites and the interaction between BRCA1 and PALB2 is important for the homologous recombination repair. Taken together, our results indicate that BRCA1 is an upstream regulator of BRCA2 in the DNA-damage response, and PALB2 is the linker between BRCA1 and BRCA2.
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                Author and article information

                Journal
                BMC Med Genet
                BMC Medical Genetics
                BioMed Central
                1471-2350
                2010
                2 February 2010
                : 11
                : 20
                Affiliations
                [1 ]Department of Molecular Pathology, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
                [2 ]Department of Endocrinology, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
                [3 ]Department of Genetic Counselling, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
                [4 ]Department of Breast Tumors and Reconstructive Surgery, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
                [5 ]Department of Gynecologic Oncology, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
                [6 ]Chair and Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
                Article
                1471-2350-11-20
                10.1186/1471-2350-11-20
                2829009
                20122277
                17492b82-db35-48dd-b4d7-d6eb9212529c
                Copyright ©2010 Dansonka-Mieszkowska et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 August 2009
                : 2 February 2010
                Categories
                Research Article

                Genetics
                Genetics

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