Identification of single nucleotide polymorphisms of the PI3K-AKT-mTOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer

IntroductionThe PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients.MethodsThe GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6).ResultsOf 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis .ConclusionPI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.     

PI3K-AKT-mTOR pathway and cancer

PI3K/AKT/mTOR pathway is an intracellular signalling pathway composed of different kinases. Many protein mutations are described in that pathway, and are responsible of dysregulation of cell growth, proliferation, survival and angiogenesis. Rapamycin is an antibiotic inhibiting mTOR. Different analogs of rapamycin are developed or being developed in antitumoral therapy, in which temsirolimus, everolimus and deforolimus, demonstrated antitumoral activity in renal cancer and mantle cell lymphoma, and many clinical trials are in progress in other tumors. In the future, predictive factors of response need to be identified; patient selection and associations with chemotherapy or with other targeted therapies should be explored.     

FGFR3基因单核苷酸多态与绝经前乳腺癌易感性的关联研究

目的 探讨FGFR3基因单核苷酸多态(SNPs)与女性绝经前乳腺癌的风险关系。方法 采用多重单碱基延伸SNP分型技术(Snapshot)检测FGFR3基因的rs2234909和rs3135848的SNP基因型在绝经前乳腺癌患者和绝经前正常女性人群中的频率,并分析不同SNP基因型与绝经前乳腺癌发病的风险关系。结果 FGFR3基因rs2234909和rs3135848的SNP基因型的频率在乳腺癌与对照组间无统计学差异(P＞0.05)。Logistic回归分析结果显示,对于rs2234909位点,相比较于TT基因型,TC和TC+CC基因型和乳腺癌的发病风险无显著相关性(OR=1.035,95% CI:0.680~1.575,P=0.874;OR=0.985,95% CI:0.638~1.521,P=0.945);对于rs3135848位点,相比较于TT基因型,TC、CC和TC+CC基因型与乳腺癌的发病风险无关(OR=1.177,95% CI:0.846~1.636,P=0.333;OR=0.948,95% CI:0.287~3.137,P=0.931;OR=1.162,95% CI:0.548~1.112,P=0.360)。rs2234909位点突变的乳腺癌患者与未突变者相比,组织学分级(显性模型:P=0.032;共显性模型:P=0.024)以及Ki67指数(显性模型:P=0.056;共显性模型:P=0.044)显著增高;rs3135848位点突变及两位点均突变与乳腺癌患者临床病理特征无显著相关性(P＞0.05)。结论 FGFR3基因的rs2234909和rs3135848两位点基因多态性与乳腺癌易感性无明显相关性;而rs2234909位点突变在绝经前乳腺癌患者中与组织学分级和Ki67指数呈正相关,可能提示预后不良。     

PI3K-AKT-mTOR信号通路抑制剂与肿瘤免疫治疗

磷脂酰肌醇3-蛋白激酶B-哺乳动物雷帕霉素靶蛋白（PI3K-AKT-mTOR）信号通路的上游通路主要包括表皮生长因子受体(EGFR)、人类表皮生长因子受体2(HER2)、肝细胞生长因子受体(MET)和成纤维细胞生长因子受体(FGFR)等各类受体的酪氨酸激酶,其受体的突变、扩增常会导致PI3K-AKT-mTOR信号通路的失调,引起肿瘤发生发展。该通路异常激活常伴随着下游关键分子的改变包括PIK3CA、AKT1、PTEN 的基因突变,PIK3CA、AKT1、AKT2 的基因扩增,肿瘤抑制基因PTEN 的缺失等。PI3K-AKT-mTOR信号通路抑制剂主要包括PI3K抑制剂、AKT抑制剂、mTOR抑制剂和双重抑制剂等。PI3K-AKT-mTOR抑制剂对肿瘤免疫微环境、免疫细胞均有显著影响。PI3K-AKT-mTOR抑制剂单药治疗肿瘤具有一定局限性,如联合DC疫苗、免疫检查点抑制剂和CAR-T细胞等免疫疗法可增强抗肿瘤疗效。     

XPD基因单核苷酸多态性与乳腺癌易感性Meta分析

目的既往关于核苷酸剪切修复通路中,着色性干皮病基因D(xeroderma pigmentosum group D,XPD)基因单核苷酸多态性Lys751Gln和Arg156Arg与乳腺癌易感性关系研究的结论存在争议。本研究采用Meta分析方法定量评价Lys751Gln和Arg156Arg与乳腺癌易感性关系。方法全面检索CNKI、万方、Pubmed、Cochrane Library和EMBASE数据库中关于Lys751Gln、Arg156Arg与乳腺癌易感性关系的文献,Rev Man 5.0和StataSE 12.0软件进行Meta分析,合并OR值及95%CI绘制森林图。逐一剔除每项研究进行敏感性分析,漏斗图法和Begger’s检验判断发表偏倚,假阳性结果报告率(false positive report probability,FPRP)评价假阳性错误概率。结果共纳入37篇文献,包括17 692例乳腺癌患者和18 325例对照。Lys751Gln位点CC基因型相对于AA基因型是乳腺癌发生的危险因素,OR=1.27,95%CI为1.07~1.50,P=0.01,FPRP值为0.043;显性模型OR=1.13,95%CI为1.02~1.24,P=0.02,FPRP值为0.082;隐性模型OR=1.24,95%CI为1.05~1.46,P=0.01,FPRP值为0.082。亚组分析结果中发现,仅在非亚洲人群中该关联差异有统计学意义,AC相对于AA,OR=1.07,95%CI为1.01~1.13,P=0.01;CC相对于AA,OR=1.30,95%CI为1.08~1.57,P=0.01;显性模型OR=1.17,95%CI为1.04~1.31,P=0.01;隐性模型OR=1.26,95%CI为1.05~1.52,P=0.01。未得到Arg156Arg位点与乳腺癌发生有意义的结果,P>0.05。结论 XPD基因Lys751Gln位点与乳腺癌的发生存在一定的关联,尚未发现Arg156Arg位点与乳腺癌的发病有关。     

TOX3基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险关联的研究

目的:探讨TOX3基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险的关系。方法:采用多重单碱基延伸单核苷酸多态性分型技术(Snapshot)分析方法,检测280例绝经前的乳腺癌患者和287例绝经前的正常对照者TOX3基因rs3803662和rs12443621多态性位点基因型,并比较不同基因型与乳腺癌风险的关系。结果:TOX3基因rs3803662和rs12443621多态性位点基因型频率,在乳腺癌病例组和对照组之间差异无统计学意义,P值分别为0.718和0.340。Logistic回归分析结果显示,对于rs3803662位点,与GG基因型相比,GA、AA和GA+AA基因型与乳腺癌的危险性无关(OR=0.846,95%CI:0.489～1.463,P=0.549;OR=0.802,95%CI:0.470～1.368,P=0.418;OR=0.821,95%CI:0.492～1.368,P=0.449);对于rs12443621位点,与GG基因型相比,GA、AA和GA+AA基因型与乳腺癌的危险性无关(OR=0.755,95%CI:0.518～1.099,P=0.755;OR=0.850,95%CI:0.528～1.368,P=0.504;OR=0.781,95%CI:0.548～1.112,P=0.170)。结论:在目前样本条件下,TOX3基因rs3803662和rs12443621位点多态性与中国北方汉族绝经前妇女乳腺癌易感性之间无明显关联。     

Targeting the PI3K-AKT-mTOR signaling network in cancer

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.     

BRCA1相关A蛋白复合物基因单核苷酸多态性与三阴性乳腺癌易感性研究

背景与目的：BRCA1突变与三阴性乳腺癌发病相关目前已得到学者公认。该研究旨在分析BRCA1相关A蛋白复合物相关基因的单核苷酸多态性(single nucleotide polymorphisms,SNP)与三阴性乳腺癌发病风险的关系,寻找和确定与汉族人群三阴性乳腺癌遗传易感性相关的基因型和单体型。方法：2008年-2011年间414例在复旦大学附属肿瘤医院接受原发性乳腺癌手术的三阴性乳腺癌患者和354例健康妇女进入本病例对照研究。通过对Abraxas、BRE、Rap80、NBA1和BRCC36基因组DNA的37个SNP位点的检测,分析它们与三阴性乳腺癌的相关性。研究者随后检测了652例其他类型乳腺癌和890例健康女性的DNA以证实发现的SNP是否为三阴性特有的遗传相关位点。结果：该研究在第一步研究中发现,NBA1启动子区rs7250266位点突变的G等位基因在三阴性乳腺癌患者中的频率显著低于在正常女性中的频率(0.14 vs 0.19,P<0.01)。对rs7250266位点基因分型显示：与携带CC基因型个体比较,携带GC型个体的三阴性乳腺癌的发病风险显著降低(GC∶OR=0.70,95%CI：0.51~0.97;GG∶OR=0.48,95%CI：0.21~1.07,P=0.03)。单体型分析也证实NBA1基因的不同单体型间三阴性乳腺癌发病风险不同。第二步的研究结果显示,rs7250266位点突变在非三阴性的乳腺癌与正常人群中差异无统计学意义(0.19 vs 0.18,P=0.85)。结论：NBA1基因的rs7250266位点的单核苷酸多态性与汉族女性的三阴性乳腺癌发病风险相关,其突变型等位基因携带者罹患三阴性乳腺癌的风险低于野生型等位基因携带者。     

PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中的活化

目的 探讨PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中的活化情况.方法 收集13例伯基特淋巴瘤患者淋巴瘤组织及14例患者淋巴结反应性增生组织病理切片,采用免疫组织化学方法检测AKT、mTOR、RPS6磷酸化情况.结果 伯基特淋巴瘤组织中p-AKT、p-mTOR、p-RPS6表达率分别为84.6％(11/13)、100.0％(13/13)、100.0％(13/13),反应性淋巴结增生为64.2 ％(9/14)、71.4％(10/14)、78.6 ％(11/14),阳性表达率差异均具有统计学意义(均P＜0.05).结论 PI3K-AKT-mTOR信号通路在伯基特淋巴瘤中存在异常活化.     

中国汉族人群DNA聚合酶ε基因POLE1单核苷酸多态性与肺癌易感性的关系

目的：探讨人类DNA聚合酶ε基因POLE1单核苷酸多态性（SNP）与肺癌易感性间的关系。方法：采用病例对照研究方法,选择经组织学确诊的肺癌患者462例,以及相同地区,性别年龄频数匹配的对照466例,针对经筛选的5个SNP进行基因型检测,通过统计分析研究基因频率与肺癌风险的关系,并探讨吸烟在其中的影响。结果：病例组rs5744738基因频率分布高于对照组（P〈0.05）。A/A纯合变异携带人群的患肺癌风险显著降低（校正OR=0.47,95%CI：0.25～0.91）。在分层分析中,60岁以上人群患肺癌的风险显著下降（校正OR=0.28,95%CI：0.09～0.91）,无患肿瘤家族史人群下降到0.42倍（校正OR=0.42,95%CI：0.19～0.90）。随着吸烟量的增加,G/G或G/A基因型人群肺癌风险显著升高。rs5744962变异位点（T→C）可提高非吸烟人群的患肺癌风险至1.75倍（95%CI：1.02～3.00）。结论：选取的5个人类POLE1基因SNP的多态性可能与中国汉族人群肺癌遗传易感性有关,在携带rs5744738及与之紧密连锁的rs4883545、rs5744873突变纯合基因的人群,患肺癌的风险显著降低,而携带rs5744962、rs5745047突变基因位点的非吸烟人群患肺癌的风险升高。     

The role of single nucleotide polymorphisms in breast cancer metastasis

Our understanding of many aspects of cancer biology has been advanced through the use of modern genetics. These studies have already shown that germ line polymorphisms play a significant role in disease initiation and response to therapy. However, what is less well studied is the role of germ line polymorphisms in cancer progression. Studies in rodents indicate that differential susceptibility to cancer metastasis can be heritable; thus, the search for the genes that control cancer metastasis is underway. Although some provocative studies suggest potential candidates for metastasis regulating genes, the conclusive identification of a specific inherited genetic variant that alters metastatic potential awaits further studies.     

PTEN基因单核苷酸多态性与乳腺癌的关系

目的:研究PTEN基因-9C/G单核苷酸多态性与中国汉族女性人群乳腺癌之间的相关性。方法:采用基于人群的病例-对照研究,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型,检测210例中国汉族女性乳腺癌患者和210例健康女性的PTEN基因-9C/G多态性。结果:PTEN基因-9C/G位点(rs11202592)多态性基因型分布频率在两组间比较无显著性差异(P=0.862)。PTEN基因-9C/G单核甘酸多态性不同基因型间在ER、Her-2表达上无显著性差异(P>0.05)。结论:PTEN基因-9C/G位点多态性与中国汉族女性乳腺癌易感性无明显关联,ER、HER-2表达同此位点多态性也无明显关联。     

Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival

The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.     

The adenosine-A2a receptor regulates the radioresistance of gastric cancer via PI3K-AKT-mTOR pathway

International Journal of Clinical Oncology - Radiotherapy is a key strategy in gastric cancer (GC) treatment. However, radioresistance remains a serious concern. It is unclear whether the...     

Targeting the PI3-kinase pathway in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the phosphoinositide 3 (PI3)-kinase and AKT signalling pathway is one of the most frequent oncogenic aberrations of TNBC. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in phosphatase and tensin homologue, occur in ∼25%‒30% of advanced TNBC. Recent randomised trials suggest improved progression-free survival (PFS) with AKT-inhibitors in combination with first-line chemotherapy for patients with TNBC and pathway genetic aberrations. We review the evidence for PI3K pathway activation in TNBC, and clinical trial data for PI3K, AKT and mammalian target of rapamycin inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.     

Association of five single nucleotide polymorphisms at 6q25.1 with breast cancer risk in northwestern China

CCDC170 and ESR1, located at 6q25.1, were associated with breast cancer (BC) risk by genome-wide association studies. Our goal was to validate the association between CCDC170-ESR1 polymorphisms and BC risk in the population of northwestern China. A case-control study of 551 patients with BC and 577 control individuals was conducted from January 2011 to November 2014. We analyzed five BC-associated single nucleotide polymorphisms (SNPs) identified in CCDC170-ESR1 by previous studies. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals after adjusting for body mass index and age. The minor alleles of rs3757318, rs3734805, and rs2046210 were associated with increased BC risk (OR = 1.30, p = 0.005; OR = 1.28, p = 0.006; OR = 1.20, p = 0.033, respectively) in an allelic model analysis. Those three SNPs had a coincident significant association with increased BC risk in genetic models and stratification analyses. A new haplotype, “CT”, was associated with a 1.31-fold increased risk of BC (OR = 1.31, p = 0.006). The “C” allele of rs9383951 was associated with a reduced risk of BC (OR = 0.69, p = 0.048) in estrogen receptor-positive individuals under the log-additive model. Our data provide new evidence of the association between CCDC170-ESR1 and BC susceptibility in the population of northwestern China.     

Single nucleotide polymorphisms in breast cancer

A limited number of genes have been identified that explain heritable risks of breast cancer (BC). We searched for low-penetrant genes in an association study using two populations: 223 Finnish unselected patients and 172 Polish familial cases, both with locally collected healthy controls. Candidate genes included DNA repair genes, methylenetetrahydrofolate reductase (MTHFR) and cyclin D1 genes. The frequencies for single nucleotide polymorphisms (SNPs) were measured in the following genes: NBS1, XPC, XPD, XRCC1, XRCC3, MTHFR, and cyclin D1. Odds ratios (ORs) were calculated to the wild-type genotype. The positive findings in the Finnish series were repeated in the Polish series. Significant findings among Finns were associations to XPC exon 15, XPD exon 10 and XRCC3 exon 7, the latter of borderline significance. None of these results could be repeated in the Polish series. The XPC result among Finns was probably an artifact of the control group deviating from the Hardy-Weinberg Equilibrium (HWE). The attempt to repeat the result for the XPD polymorphism among Poles was probably not valid because the control group deviated from the HWE. We conclude that within statistical power of the present study, none of the tested polymorphisms associated with BC, with the probable exception of XPD.     

FGFR1基因单核苷酸多态性与中国北方汉族女性乳腺癌发病风险及临床病理特征的关系

目的:探究成纤维生长因子受体1（fibroblast growth factor receptor-1,FGFR1)基因单核苷酸多态性与中国北方汉族女性乳腺癌发病风险和临床病理特征的相关性。方法:采用多重单碱基延伸单核苷酸多态性分型技术检测747例乳腺癌患者和716例健康女性人群FGFR1基因rs13317和rs3213849多态位点基因型,并比较不同基因型与乳腺癌发病风险和临床病理特征的关系。结果:FGFR1基因rs13317和rs3213849多态位点基因型频率在乳腺癌组和对照组中的分布无统计学差异(P＞0.05)。与TT基因型携带者相比,rs13317位点的CT基因型、CC基因型和CT+CC基因型携带者与乳腺癌发病风险无关(P=0.464、P=0.136、P=0.103)。与GG基因型携带者相比,rs3213849位点的GA基因型、AA基因型和GA+AA基因型携带者与乳腺癌发病风险无关(P=0.642、P=0.222、P=0.416)。临床病理分析结果显示,rs13317位点多态性与乳腺癌患者的临床分期、肿瘤大小、组织学分级、淋巴结转移、ER、PR、HER2、Ki67及p53无关(P＞0.05)。在共显性模型下,rs3213849位点在Ki67分布上可能存在差异(P=0.055);在显性模型下,rs3213849位点与Ki67表达情况具有相关性(P=0.023),与其他临床病理因素之间均不相关(P＞0.05)。结论:在目前的样本条件下,FGFR1基因rs3213849位点与Ki67表达可能相关,而rs13317和rs3213849多态性与中国北方汉族女性乳腺癌易感性及其他临床病理特征之间无明显相关性。     

Association of genetic polymorphisms in the VEGF gene with breast cancer survival

The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. VEGF overexpression has been associated with advanced stage and poor survival of several cancers. We evaluated the association of functional polymorphisms in the VEGF gene with breast cancer survival in a cohort of 1,193 breast cancer patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and followed for cancer recurrence and mortality between March 2000 and December 2002. Included in the study were three functional polymorphisms (C-460T, G+405C, and C+936T) in the VEGF gene. Carrying the -460C or +405G allele was associated with decreased overall survival. The age-adjusted hazard ratios (HR) were 1.5 [95% confidence interval (95% CI), 0.9-2.5] for -460CC genotype carriers and 1.6 (95% CI, 1.0-2.5) for +405GG genotype carriers compared with noncarriers. Further analyses showed that the -460T/+450C/+936C haplotype was related to increased survival (HR, 0.57; 95% CI, 0.4-0.9), whereas the -460C/+405G/+936T haplotype was associated with nonsignificantly decreased survival (HR, 2.1; 95% CI, -0.9 to 4.7). The C+936T polymorphism alone was not related to overall or disease-free survival. This study suggests that VEGF polymorphisms may be a significant genetic marker for breast cancer prognosis.