背景与目的:PALB2基因是新近发现的乳腺癌易感基因,其多个遗传单核苷酸多态性(SNP)可能与乳腺癌发病风险有关,本研究探讨PALB2基因rs249954、rs447529及rs16940342多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性。...背景与目的:PALB2基因是新近发现的乳腺癌易感基因,其多个遗传单核苷酸多态性(SNP)可能与乳腺癌发病风险有关,本研究探讨PALB2基因rs249954、rs447529及rs16940342多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性。方法:对124例早发性乳腺癌患者(年龄≤35岁)和101例健康女性进行PALB2基因rs249954、rs447529及rs16940342 PCR扩增,并采用基质辅助激光解吸电离飞行时间质谱分析(MALDI-TOF-MS)法鉴定其基因型,比较各基因型分布和发病风险的关系;应用非条件Logistic回归分析计算危险度(OR)及95%CI。结果:PALB2基因rs249954、rs447529及rs16940342多态性基因型在病例组中的分布频率与对照组的分布频率均未见明显差异(P>0.05)。Logistic回归分析表明,在早发性乳腺癌人群中,以rs249954的CC基因型、rs447529 CC基因型及rs16940342 AA基因型为参照,各基因多态性位点的其他基因型,均未能显著改变乳腺癌的发病危险(P>0.05)。各基因型风险比分别为1.061(rs249954 TT vs CC),0.793(rs447529 GG vs CC)以及0.921(rs16940342 GG vs AA)。结论:PALB2基因rs249954、rs447529及rs16940342多态性可能与福建地区汉族人群早发性乳腺癌的遗传易感性无关,作为低外显率的乳腺癌易感基因位点和未来临床基因筛查的候选指标尚需谨慎。展开更多
BRCA2(Breast cancer susceptibility gene 2)的伴侣和定位子(Partner and localizer of BRCA2,PALB2)对DNA双链断裂(Double-strand breaks,DSBs)引起的同源重组(Homologous recombinant,HR)修复至关重要。PALB2作为一种肿瘤抑制因子参...BRCA2(Breast cancer susceptibility gene 2)的伴侣和定位子(Partner and localizer of BRCA2,PALB2)对DNA双链断裂(Double-strand breaks,DSBs)引起的同源重组(Homologous recombinant,HR)修复至关重要。PALB2作为一种肿瘤抑制因子参与维持基因组完整性,在同源定向修复过程中协调BRCA1(Breast cancer susceptibility gene 1)和BRCA2的功能,并与多种染色质蛋白相互作用。在HR过程中,PALB2在BRCA1和BRCA2之间起着重要的桥梁作用,促进RAD51重组酶向DNA损伤位点的募集并将其组装成核丝以启动DSBs修复。本文综述了PALB2蛋白的生物学作用及其调控的研究进展,并描述了PALB2乳腺癌易感性、侵袭性临床病理特征与不良临床预后之间的联系,讨论其纳入遗传咨询和患者治疗方案中所遇到的机遇和挑战。展开更多
目的探究乳腺癌易感基因PALB2 rs249954位点单核苷酸多态性与乳腺癌发病风险的关系。方法检索中国知网(CNKI)、万方、中国生物医学文献数据库(CBM)、Pub Med、Embase、Cochrane Library、Science Direct及Web of Science数据库,搜索国...目的探究乳腺癌易感基因PALB2 rs249954位点单核苷酸多态性与乳腺癌发病风险的关系。方法检索中国知网(CNKI)、万方、中国生物医学文献数据库(CBM)、Pub Med、Embase、Cochrane Library、Science Direct及Web of Science数据库,搜索国内外有关乳腺癌PALB2 rs249954位点单核苷酸多态性的文献,依据纳入标准、排除标准以及质量评价原则,筛选出符合要求的文献,使用Stata 14.0软件进行meta分析并对发表偏移进行评估。结果共纳入7篇符合要求的研究,累积乳腺癌病例3 247例,累积对照3 294例。meta分析结果显示,等位基因模型[T vs C:OR=1.14,95%CI为(0.95,1.37),P=0.156]、显性基因模型[CT+TT vs CC:OR=1.22,95%CI为(0.97,1.54),P=0.088]、隐性基因模型[TT vs CT+CC:OR=1.11,95%CI为(0.84,1.45),P=0.464]、共显性基因模型CC vs TT[OR=0.79,95%CI为(0.54,1.15),P=0.226]及共显性基因模型TT vs CT[OR=0.95,95%CI为(0.82,1.11),P=0.523]的合并OR值均无统计学意义;共显性基因模型CC vs CT[OR=0.82,95%CI为(0.67,1.00),P=0.048]的合并OR值具有统计学意义,但敏感性分析示结果不具有稳定性;超显性基因模型的合并OR值具有统计学意义[CC+TT vs CT:OR=0.85,95%CI为(0.77,0.94),P=0.001],相比于CC+TT,CT杂合子基因型可增加乳腺癌的发病风险。结论 PALB2 rs249954位点的突变型CT杂合子基因型相对于CC+TT基因型可增加乳腺癌的发病风险。展开更多
The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse ...The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brcal,Brca2 and Palb2 conditional knockout models,it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis.Here,we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds.Rather than mammary tumors,Palb2 and Trp53 compound mutant mice developed,with greatly reduced latencies,lymphomas and sarcomas that are typically associated with germline Trp53 inactivation.Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice.These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development,possibly without altering the fundamental tumorigenic processes.展开更多
Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on ou...Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several largevolume centers have initiated such screening protocols, and consensus-based guidelines for screening high-riskgroups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.展开更多
文摘背景与目的:PALB2基因是新近发现的乳腺癌易感基因,其多个遗传单核苷酸多态性(SNP)可能与乳腺癌发病风险有关,本研究探讨PALB2基因rs249954、rs447529及rs16940342多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性。方法:对124例早发性乳腺癌患者(年龄≤35岁)和101例健康女性进行PALB2基因rs249954、rs447529及rs16940342 PCR扩增,并采用基质辅助激光解吸电离飞行时间质谱分析(MALDI-TOF-MS)法鉴定其基因型,比较各基因型分布和发病风险的关系;应用非条件Logistic回归分析计算危险度(OR)及95%CI。结果:PALB2基因rs249954、rs447529及rs16940342多态性基因型在病例组中的分布频率与对照组的分布频率均未见明显差异(P>0.05)。Logistic回归分析表明,在早发性乳腺癌人群中,以rs249954的CC基因型、rs447529 CC基因型及rs16940342 AA基因型为参照,各基因多态性位点的其他基因型,均未能显著改变乳腺癌的发病危险(P>0.05)。各基因型风险比分别为1.061(rs249954 TT vs CC),0.793(rs447529 GG vs CC)以及0.921(rs16940342 GG vs AA)。结论:PALB2基因rs249954、rs447529及rs16940342多态性可能与福建地区汉族人群早发性乳腺癌的遗传易感性无关,作为低外显率的乳腺癌易感基因位点和未来临床基因筛查的候选指标尚需谨慎。
文摘BRCA2(Breast cancer susceptibility gene 2)的伴侣和定位子(Partner and localizer of BRCA2,PALB2)对DNA双链断裂(Double-strand breaks,DSBs)引起的同源重组(Homologous recombinant,HR)修复至关重要。PALB2作为一种肿瘤抑制因子参与维持基因组完整性,在同源定向修复过程中协调BRCA1(Breast cancer susceptibility gene 1)和BRCA2的功能,并与多种染色质蛋白相互作用。在HR过程中,PALB2在BRCA1和BRCA2之间起着重要的桥梁作用,促进RAD51重组酶向DNA损伤位点的募集并将其组装成核丝以启动DSBs修复。本文综述了PALB2蛋白的生物学作用及其调控的研究进展,并描述了PALB2乳腺癌易感性、侵袭性临床病理特征与不良临床预后之间的联系,讨论其纳入遗传咨询和患者治疗方案中所遇到的机遇和挑战。
文摘目的探究乳腺癌易感基因PALB2 rs249954位点单核苷酸多态性与乳腺癌发病风险的关系。方法检索中国知网(CNKI)、万方、中国生物医学文献数据库(CBM)、Pub Med、Embase、Cochrane Library、Science Direct及Web of Science数据库,搜索国内外有关乳腺癌PALB2 rs249954位点单核苷酸多态性的文献,依据纳入标准、排除标准以及质量评价原则,筛选出符合要求的文献,使用Stata 14.0软件进行meta分析并对发表偏移进行评估。结果共纳入7篇符合要求的研究,累积乳腺癌病例3 247例,累积对照3 294例。meta分析结果显示,等位基因模型[T vs C:OR=1.14,95%CI为(0.95,1.37),P=0.156]、显性基因模型[CT+TT vs CC:OR=1.22,95%CI为(0.97,1.54),P=0.088]、隐性基因模型[TT vs CT+CC:OR=1.11,95%CI为(0.84,1.45),P=0.464]、共显性基因模型CC vs TT[OR=0.79,95%CI为(0.54,1.15),P=0.226]及共显性基因模型TT vs CT[OR=0.95,95%CI为(0.82,1.11),P=0.523]的合并OR值均无统计学意义;共显性基因模型CC vs CT[OR=0.82,95%CI为(0.67,1.00),P=0.048]的合并OR值具有统计学意义,但敏感性分析示结果不具有稳定性;超显性基因模型的合并OR值具有统计学意义[CC+TT vs CT:OR=0.85,95%CI为(0.77,0.94),P=0.001],相比于CC+TT,CT杂合子基因型可增加乳腺癌的发病风险。结论 PALB2 rs249954位点的突变型CT杂合子基因型相对于CC+TT基因型可增加乳腺癌的发病风险。
基金This work was supported by the National Cancer Institute(R01CA138804 to BX,R01GM129066 to SD,P30CA072720 to Rutgers Cancer Institute of New Jersey,and P30CA008748 to MSKCC).AHM was supported by Higher Committee for Education Development(HCED)of Iraq.
文摘The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brcal,Brca2 and Palb2 conditional knockout models,it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis.Here,we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds.Rather than mammary tumors,Palb2 and Trp53 compound mutant mice developed,with greatly reduced latencies,lymphomas and sarcomas that are typically associated with germline Trp53 inactivation.Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice.These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development,possibly without altering the fundamental tumorigenic processes.
文摘Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several largevolume centers have initiated such screening protocols, and consensus-based guidelines for screening high-riskgroups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.
