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Ranjit Manchanda - One of the best experts on this subject based on the ideXlab platform.
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cost effectiveness of population based brca1 brca2 rad51c rad51d brip1 PALB2 mutation testing in unselected general population women
Journal of the National Cancer Institute, 2018Co-Authors: Shreeya Patel, Vladimir S Gordeev, Antonis C Antoniou, Shantel Smith, Ranjit Manchanda, John L. Hopper, Robert J MacinnisAbstract:Background: The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women. Methods: A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer. Results: Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million. Conclusions: Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.
Dai Kitagawa - One of the best experts on this subject based on the ideXlab platform.
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mutation status of rad51c PALB2 and brip1 in 100 japanese familial breast cancer cases without brca1 and brca2 mutations
Cancer Science, 2017Co-Authors: Katsutoshi Sato, Mio Koyasu, Sachio Nomura, Yuri Sato, Mizuho Kita, Yuumi Ashihara, Yasue Adachi, Shinji Ohno, Takuji Iwase, Dai KitagawaAbstract:Summary In addition to BRCA1 and BRCA2, RAD51C, PALB2, and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not been evaluated yet. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2, and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exon 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G, and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries. This article is protected by copyright. All rights reserved.
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Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.
Cancer Science, 2017Co-Authors: Katsutoshi Sato, Mio Koyasu, Sachio Nomura, Yuri Sato, Mizuho Kita, Yuumi Ashihara, Yasue Adachi, Shinji Ohno, Takuji Iwase, Dai KitagawaAbstract:In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.
William D. Foulkes - One of the best experts on this subject based on the ideXlab platform.
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Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Genetics in Medicine, 2021Co-Authors: Marc Tischkowitz, Judith Balmana, William D. Foulkes, Paul James, Joanne Ngeow, Rita Schmutzler, Nicoleta Voian, Myra J. Wick, Douglas R. Stewart, Tuya PalAbstract:Purpose PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited. Methods A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors. Results PALB2 heterozygotes should be offered BRCA1/2 -equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1 / 2 . Conclusion This guidance is similar to those for BRCA1 / 2 . While the range of the cancer risk estimates overlap with BRCA1/2 , point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.
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abstract 2335 heterozygous PALB2 mutations cause replication stress and dna repair defects in carrier derived lymphoblastoid cell lines
Epidemiology, 2020Co-Authors: Niina Laurila, Bing Xia, Katri Pylkäs, Muthiah Bose, Kerstin Borgmann, Helmut Pospiech, William D. Foulkes, Melissa C. Southey, Felix Meyer, Robert WinqvistAbstract:During the last decade, PALB2 has been defined as a high-risk breast cancer susceptibility gene alongside BRCA1 and BRCA2. Heterozygous mutation in PALB2 increases the lifetime breast cancer risk of female carriers to an average of 53%, but the risk estimate is affected by family history, studied population, and the specific pathogenic variant. We have previously shown that lymphoblastoid cell lines (LCLs) of persons heterozygous for PALB2 c.1592delT, a Finnish founder mutation, show defects in DNA replication and damage response. Now we examine how various heterozygous, protein-truncating PALB2 founder mutations from different populations affect cell function, and whether the observed phenotype correlates with disease risk. The study cohorts come from Canada, Australia, and Finland and consist of 80 LCLs of PALB2 mutation carriers (c.1592delT, c.2323C>T, c.3113G>A or c.3323delA) and suitable population controls. There is some evidence that these variants are associated with different magnitudes of breast cancer risk, and PALB2 c.3113G>A has been associated with an exceptionally high cancer risk of 91% (95% CI 44-100) to age 70. Utilizing these LCLs, we have studied DNA damage response, cell cycle progression, and DNA replication with various methods. DNA fiber assay results show that PALB2 mutation carriers elongate their DNA more slowly during replication, likely due to increased fork stalling, but compensate this by increased dormant origin firing. The strongest replication phenotype was observed for PALB2 c.3113G>A carriers. High content analysis shows that most of the mutation carriers had compromised RAD51 foci formation after DNA damage, whereas 53BP1 foci levels were elevated. These results indicate that during DNA double-strand break repair, heterozygous PALB2 mutation carriers may rely more on alternative, error-prone pathways that are independent of RAD51, thus contributing to genomic instability. Additionally, we are currently performing RNA-Seq to determine if the LCLs show adaptation of their gene expression in response to pathogenic PALB2 variants. Citation Format: Niina Laurila, Kerstin Borgmann, Muthiah Bose, Felix Meyer, Katri Pylkas, Bing Xia, William Foulkes, Melissa Southey, Helmut Pospiech, Robert Winqvist. Heterozygous PALB2 mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2335.
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rare germline mutations in PALB2 and breast cancer risk a population based study
Human Mutation, 2012Co-Authors: Marinela Capanu, Nelly Sabbaghian, William D. Foulkes, Xiaolin Liang, Maxime Vallee, Sean V Tavtigian, Patrick ConcannonAbstract:Germline mutations in the PALB2 gene are associated with an increased risk of developing breast but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (p=0.04). The first degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of non-carrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3 fold increase in risk (95% CI: 1.8–13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 versus 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.
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identification of a novel truncating PALB2 mutation and analysis of its contribution to early onset breast cancer in french canadian women
Breast Cancer Research, 2007Co-Authors: William D. Foulkes, Nelly Sabbaghian, Parviz Ghadirian, Mohammed Reza Akbari, Nancy Hamel, Sylvie Giroux, Andrew Darnel, Robert Royer, Aletta PollAbstract:PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.
Robert J Macinnis - One of the best experts on this subject based on the ideXlab platform.
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cost effectiveness of population based brca1 brca2 rad51c rad51d brip1 PALB2 mutation testing in unselected general population women
Journal of the National Cancer Institute, 2018Co-Authors: Shreeya Patel, Vladimir S Gordeev, Antonis C Antoniou, Shantel Smith, Ranjit Manchanda, John L. Hopper, Robert J MacinnisAbstract:Background: The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women. Methods: A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer. Results: Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million. Conclusions: Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.
Bing Xia - One of the best experts on this subject based on the ideXlab platform.
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abstract 2335 heterozygous PALB2 mutations cause replication stress and dna repair defects in carrier derived lymphoblastoid cell lines
Epidemiology, 2020Co-Authors: Niina Laurila, Bing Xia, Katri Pylkäs, Muthiah Bose, Kerstin Borgmann, Helmut Pospiech, William D. Foulkes, Melissa C. Southey, Felix Meyer, Robert WinqvistAbstract:During the last decade, PALB2 has been defined as a high-risk breast cancer susceptibility gene alongside BRCA1 and BRCA2. Heterozygous mutation in PALB2 increases the lifetime breast cancer risk of female carriers to an average of 53%, but the risk estimate is affected by family history, studied population, and the specific pathogenic variant. We have previously shown that lymphoblastoid cell lines (LCLs) of persons heterozygous for PALB2 c.1592delT, a Finnish founder mutation, show defects in DNA replication and damage response. Now we examine how various heterozygous, protein-truncating PALB2 founder mutations from different populations affect cell function, and whether the observed phenotype correlates with disease risk. The study cohorts come from Canada, Australia, and Finland and consist of 80 LCLs of PALB2 mutation carriers (c.1592delT, c.2323C>T, c.3113G>A or c.3323delA) and suitable population controls. There is some evidence that these variants are associated with different magnitudes of breast cancer risk, and PALB2 c.3113G>A has been associated with an exceptionally high cancer risk of 91% (95% CI 44-100) to age 70. Utilizing these LCLs, we have studied DNA damage response, cell cycle progression, and DNA replication with various methods. DNA fiber assay results show that PALB2 mutation carriers elongate their DNA more slowly during replication, likely due to increased fork stalling, but compensate this by increased dormant origin firing. The strongest replication phenotype was observed for PALB2 c.3113G>A carriers. High content analysis shows that most of the mutation carriers had compromised RAD51 foci formation after DNA damage, whereas 53BP1 foci levels were elevated. These results indicate that during DNA double-strand break repair, heterozygous PALB2 mutation carriers may rely more on alternative, error-prone pathways that are independent of RAD51, thus contributing to genomic instability. Additionally, we are currently performing RNA-Seq to determine if the LCLs show adaptation of their gene expression in response to pathogenic PALB2 variants. Citation Format: Niina Laurila, Kerstin Borgmann, Muthiah Bose, Felix Meyer, Katri Pylkas, Bing Xia, William Foulkes, Melissa Southey, Helmut Pospiech, Robert Winqvist. Heterozygous PALB2 mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2335.
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abstract mip 049 atr dependent regulation of the ovarian cancer protein PALB2 at dna double strand breaks
Clinical Cancer Research, 2017Co-Authors: Rémi Buisson, Jean-yves Masson, Amelie Rodrigue, Bing Xia, Niraj Joshi, Tzeh Keong Foo, Emilie J L Hardy, Wilhelm Haas, Lee ZouAbstract:Cancer is a constant threat to humans since one out of three individuals will develop cancer during their lifetime. It has become increasingly clear that tumor formation can be triggered by mutations in enzymes involved in the surveillance of genome integrity, such as BRCA1, BRCA2 and PALB2. BRCA1, BRCA2 and PALB2 are essential players in double–strand break repair by homologous recombination and have been associated with a heightened lifetime risk for ovarian cancer development. Cancer cells with BRCA1/2 and PALB2 deficiency are extremely sensitive to inhibitors of the DNA repair protein PARP, which have recently emerged as promising anti–cancer drugs. However, mutations in BRCA1/2 and PALB2 account only for around 15–20 % of ovarian cancers overall. Developing new strategies to specifically target ovarian cancer is still presenting a major challenge. During homologous recombination, PALB2 links BRCA1 and BRCA2 to promote RAD51 filament formation at DNA double–strand breaks repair. PALB2 interacts directly with BRCA1 via its N–terminal coiled–coil domain and with BRCA2 via its C–terminal WD40 domain. After DNA damage, PALB2–BRCA1 interaction is enhanced to promote PALB2, BRCA2 and RAD51 localization to DNA double–strand breaks. However, how DNA damage promotes the interaction between PALB2 and BRCA1 is still not understood. In this study, we found that the phosphatidylinositol 3–kinase–like proteins kinase ATR is essential to promote PALB2 and RAD51 to DNA double–strand breaks by enhancing the interaction between PALB2 and BRCA1. We identified two functions of ATR important to enhance PALB2–BRCA1 interaction. First, ATR directly phosphorylates PALB2 on serine 59 after DNA damage. Secondly after DNA double–strand breaks resection, ATR down–regulates CDKs activity leading to the decrease of serine 64 phosphorylation on PALB2. Together, these dual events lead to a direct enhancement of the interaction between PALB2 and BRCA1. Furthermore, we generated PALB2 mutants mimicking the active and inactive state of PALB2. We showed that PALB2 phospho–mutants that recapitulated the active state of PALB2 are able to bypass the absence of ATR activity in cells while mutants that mimic the inactive state of PALB2 showed a defect even in presence of active ATR. These results explain for the first time why ATR is essential to promote DNA double–strand break repair by homologous recombination. My results suggest that that ovarian cancer cells that do not carry BRCA1/2 or PALB2 mutations may be rendered “BRCA–like” by treatment with ATR inhibitor, making them susceptible to treatments with PARPi and others DNA damaging drugs. Citation Format: Remi Buisson, Niraj Joshi, Chu Kwen Ho, Amelie Rodrigue, Tzeh Keong Foo, Emilie Hardy, Wilhelm Haas, Bing Xia, Jean–Yves Masson and Lee Zou. ATR–DEPENDENT REGULATION OF THE OVARIAN CANCER PROTEIN PALB2 AT DNA DOUBLE–STRAND BREAKS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-049.
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Heterozygous mutations in PALB2 cause DNA replication and damage response defects.
Nature communications, 2013Co-Authors: Jenni Nikkilä, Bing Xia, Ann Christin Parplys, Katri Pylkäs, Muthiah Bose, Yanying Huo, Kerstin Borgmann, Katrin Rapakko, Pentti Nieminen, Helmut PospiechAbstract:Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition.
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PALB2 synergizes with trp53 to suppress mammary tumor formation in a model of inherited breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Christian Bowmancolin, Samuel F. Bunting, Bing Xia, Rinske Drost, Christiaan Klijn, Peter Bouwman, Laura Fineman, Xixi Chen, Aedin C Culhane, Hong CaiAbstract:Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted PALB2 in the mouse. PALB2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germ-line deletion of PALB2 led to early embryonic lethality. Somatic deletion of PALB2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both PALB2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in PALB2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and PALB2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of PALB2- or Brca2-mutant primary lymphocytes. Therefore, PALB2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying PALB2 mammary tumor suppression functions can now be explored genetically in vivo.
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PALB2 fancn recombining cancer and fanconi anemia
Cancer Research, 2010Co-Authors: Marc Tischkowitz, Bing XiaAbstract:Partner and localizer of BRCA2 (PALB2) was originally identified as a BRCA2-interacting protein that is crucial for key BRCA2 genome caretaker functions. It subsequently became clear that PALB2 was another Fanconi anemia (FA) gene (FANCN), and that monoallelic PALB2 mutations are associated with increased risk of breast and pancreatic cancer. Mutations in PALB2 have been identified in breast cancer families worldwide, and recent studies have shown that PALB2 also interacts with BRCA1. Here, we summarize the molecular functions and clinical phenotypes of this key DNA repair pathway component and discuss how its discovery has advanced our knowledge of both FA and adult cancer predisposition.
