PIK3CA基因突变与乳腺癌的关系

近年来女性乳腺癌的发病率明显上升,并趋于年轻化,尽管手术治疗和术后多种辅助治疗对患者的预后有明显的改善,但仍有较高的复发率和死亡率[1]。肿瘤的发生是多因素、多阶段、多步骤、多基因改变的结果,包括原癌基因的激活和抑癌基因的失活。     

PIK3CA基因与胃癌细胞分化及侵袭力相关性研究

目的 探讨PIK3CA mRNA表达水平与胃癌细胞分化及侵袭力相关性.方法 RT-PCR和Transwell侵袭小室法分别检测三种不同分化胃癌细胞中PIK3CA mRNA表达水平及侵袭力大小.结果 PIK3CA基因表达水平越高,细胞分化程度越低,细胞侵袭力越强.结论 PIK3CA mRNA 表达水平与胃癌细胞的分化程度、侵袭力密切相关;PIK3CA基因可能参与了胃癌的分化、浸润及转移,是较好的干预治疗的靶点.     

乳腺癌 PIK3CA 基因突变与抗 HER2靶向治疗疗效的相关性

HER2阳性乳腺癌 PIK3CA 基因突变率高达25％,该基因突变能激活 PI3K-Akt 信号通路并促进 HER2介导的肿瘤细胞上皮转化,改变 HER2过表达肿瘤的内在表型,进而导致抗 HER2靶向治疗耐药。相关研究发现,PIK3CA 基因突变与抗 HER2靶向治疗疗效相关。因此,实时监测 PIK3CA 基因突变状态将有助于实现个体化抗 HER2靶向治疗。     

靶向PIK3CA突变的抗肿瘤药物研究进展

PI3K-Akt 信号通路作为肿瘤相关十大信号通路之一,在调控肿瘤恶性进展中扮演着重要角色。PIK3CA编码PI3K复合体蛋白催化亚基P110α,是一种典型的致癌突变,对实体瘤的发生和发展至关重要。PIK3CA突变可导致肿瘤对一线抗癌药物产生耐药性,其机制可能与PIK3CA突变激活PI3K-Akt 信号通路相关。目前,几种靶向PIK3CA突变的抑制剂在临床研究中取得了一定进展,特别是PI3Kα特异性抑制剂阿培利司已被FDA批准作为PIK3CA突变乳腺癌的治疗药物。本文就PIK3CA突变促进肿瘤药物耐药的机制,以及逆转耐药的治疗策略作一综述,以期更全面了解PIK3CA突变在肿瘤耐药方面的进展以及最新治疗策略。     

PIK3CA基因突变在结直肠癌中的研究进展

结直肠癌是较常见的恶性肿瘤,发病率在我国呈逐年上升趋势.肿瘤的发生是多因素、多阶段、多基因改变的结果,包括原癌基因的激活与抑癌基因的失活.PIK3 CA基因是近年发现的除KRAS突变之外的结直肠癌常见的突变基因,PI3K下游信号通路的异常活化在结直肠癌的发生过程中发挥着重要的作用.本文就PIK3CA基因的生物学作用,参与肿瘤不同阶段的发展,以及PIK3CA作为肿瘤标志物和分子靶点的潜在临床价值简要作一综述.     

胃癌患者错配修复缺陷和PIK3CA基因突变与临床病理特征的关系

目的:分析胃癌中错配修复缺陷(dMMR)和PIK3CA基因突变分别与临床病理特征的关联,以及两者之间的相关性。方法:选取本中心554例胃癌肿瘤组织标本,收集临床病理参数。免疫组化检测错配修复蛋白MSH2、MSH6、MLH1和PMS2,评判是否为dMMR。ARMS-PCR检测PIK3CA基因突变。应用统计学方法,分析dMMR和PIK3CA突变与临床病理特征的关系,以及dMMR与PIK3CA突变的关联。结果:554例胃癌患者中,dMMR 30例(5.4%)。其中,MLH1和PMS2双缺失27例(90.0%),MSH2和MSH6双缺失2例(6.7%),PMS2缺失1例（3.3%）。PIK3CA突变34例（6.1%）,其中15例E545 K (44.1%), 7例E542 K (20.1%),1例E545D(2.9%),6例H1047R(17.6%),4例H1047L(11.8%),1例E545K和E542K双突变（2.9%）。9号外显子突变24例（70.6%）,20号外显子突变10例（29.4%）。单因素分析发现,dMMR与女性,年龄> 65岁,肿瘤直径> 5 cm,肿瘤未侵及浆...     

原发小细胞肺癌中BRAF/KRAS以及PIK3CA突变的基因特征及临床特征

目的 在中国人群小细胞肺癌(SCLC)标本中检测BRAF/KRAS以及PIK3CA基因突变频率,分析这些基因突变的基因特征和临床特征。方法 2009-2014年共收集557例单纯SCLC患者组织样本。利用双脱氧测序法进行BRAF、KRAS、PIK3CA、NRAS、MEK1基因突变检测。χ²检验分析临床因素与基因突变的相关性,Kaplan-Meier法生存分析,Cox模型多因素预后分析。结果 在557例标本中检测到13例BRAF突变,突变类型包括V600E (n=5)、V600A (n=2)、V600M (n=1)、D594G (n=1)、G464E (n=1)、K601R (n=2)、S605N (n=1)。6例KRAS突变,突变类型包括G12C (n=3)、G12A (n=1)、G12D (n=1)、G13D (n=1)。4例PIK3CA突变,突变类型包括E545G (n=2)、H1047R (n=2)。另外1例NRAS突变(Q61R)和1例MEK1突变(D61Y)。这些突变基因与患者年龄、性别、吸烟状态、临床分期均无相关性。单因素生存分析结果显示基因突变组患者的生存时间比无此类突变者生存时间差,中位生存时间分别为(10.30±0.75)个月(95%CI为8.83~11.77个月)和(12.80±0.54)个月(95%CI为11.74~13.86)(P=0.011)。结论 在单纯SCLC中存在小比例的BRAF/KRAS、PIK3CA基因突变群体,这些基因突变与患者的临床特征无明显统计学相关性,但单因素生存分析显示与患者生存预后呈负相关。     

乳腺癌PIK3CA基因热点突变的研究

目的:采用突变敏感性分子开关技术,检测乳腺癌组织中PIK3CA基因热点突变的突变频率,并分析乳腺癌PIK3CA基因热点突变与乳腺癌临床病理特征之间的关系.方法:用突变敏感性分子开关技术对90例乳腺癌组织和10例乳腺纤维腺瘤组织DNA进行检测,并利用基因测序进一步验证.结果:在90例乳腺癌患者中检测出18例PIK3CA基因热点突变(突变率20％,18/90),包含A3140G突变14例(突变率15.6％,14/90)、G1633A突变3例(突变率3.3％,3/90)、GI624A突变2例(突变率2.2％,2/90),其中1例患者同时发生A3140G和G1624A突变.10例乳腺纤维腺瘤中未发现以上热点突变.PIK3CA基因突变与HER-2表达有关(x2=4.119,P=0.048),过表达者中PIK3CA基因突变率低,而与年龄分布(x2 =0.238,P=0.602)、肿瘤大小(P=1.000)、淋巴结状态(x2=3.689,P＝0.056)及ER(x2=0.957,P=0.328)、PR(x2 =0.012,P=0.914)和EGFR(x2 =0.011,P=0.916)是否表达无相关性.结论:PIK3CA基因热点突变与患者的HER-2过表达呈负相关.     

高通量测序分析PIK3CA突变型与野生型结直肠癌的肠道菌群特征

  目的  采用16S rDNA二代高通量测序技术,研究PIK3CA突变型与野生型结直肠癌患者中的肠道菌群特征。  方法  选取2016年12月至2017年12月华中科技大学同济医学院附属协和医院结直肠癌患者19例,采用 16S rDNA高通量测序技术分析PIK3CA突变型（n=4）和PIK3CA野生型（n=15）之间肿瘤组织中微生物多样性和组成差异。  结果  在门水平上,结直肠癌患者的肠道菌群主要由变形菌门、栖热菌门、放线菌门、厚壁菌门和拟杆菌门组成,占总群落的98%以上。Alpha多样性分析显示,PIK3CA突变型与野生型结直肠癌患者之间微生物多样性有显著性差异,且PIK3CA突变型患者中微生物多样性明显高于野生型。Beta多样性分析显示PIK3CA突变型与野生型结直肠癌患者的肿瘤微生物特征有显著性差异。Spearman关联网络分析结果显示,在PIK3CA野生型结直肠癌肿瘤组织中,双歧杆菌属与假单胞菌呈正相关。  结论  PIK3CA突变型与野生型结直肠癌患者肿瘤组织中的微生物群落结构有显著性差异,且PIK3CA突变患者中的肠道微生物多样性更丰富。      

miR-520a靶基因PIK3CA结合位点多态性与中国汉族人群大肠癌易感性的关联研究

背景与目的：越来越多的研究表明,微小RNA(microRNA,miRNA,miR)靶基因位点的多态性可能会影响miRNA的转录或生成能力,影响个体对肿瘤的易感性。本研究旨在探讨大肠癌患者miR-520a靶基因PIK3CA 3 ’端单核苷酸多态性(single nucleotide polymorphism,SNP)位点rs141178472与中国汉族人群大肠癌易感性之间的关系。方法：选取386例大肠癌标本作为实验组,394名年龄及性别比例匹配的非肿瘤个体作为对照组。病例对照研究检测rs141178472的分布频率。统计分析大肠癌易感性与多态性之间的关系。结果：携有rs141178472 CC基因型或C等位基因显著增加了大肠癌的发病风险(CC vs TT,OR=1.716,95%CI：1.084~2.716,P=0.022;C vs T,OR=1.258,95%CI：1.021~1.551,P=0.033)。通过检测大肠癌患者外周血单个核细胞PIK3CA的表达发现,PIK3CA mRNA的表达与SNP基因型rs141178472具有关联性。结论：miR-520a与PIK3CA 3’UTR的SNP位点rs141178472相互作用可能与大肠癌易感性有关。     

PIK3CA过表达对胃癌细胞侵袭力影响的探讨

目的:探讨PIK3CA过表达对胃癌细胞侵袭力的影响.方法:采用RT-PCR和蛋白质印迹法分别检测3种不同分化胃癌细胞HGC-27、BDC-823和SGC-7901中PIK3CA mRNA及蛋白表达水平.通过Transwell侵袭小室法检测其侵袭力,分析PTK3CA表达水平变化对胃癌细胞侵袭力的影响.结果:PIK3CAmRNA及蛋白在未分化HGC-27细胞中表达水平最高,细胞侵袭力最强(穿膜细胞数为45.24±3.16),在低分化BGC-823细胞(穿膜细胞数为22.28±1.65)及中等分化的SGC-7901细胞(穿膜细胞数为14.42±1.02)中分别次之(P<0.05).结论:PIK3CA mRNA及蛋白表达水平越高,细胞侵袭力越强,且后者随前者表达减少而减弱;PIK3CA过表达可能在胃癌细胞侵袭中起重要作用.     

The prevalence of PIK3CA mutations in gastric and colon cancer

A wide variety of tumours show PIK3CA mutations leading to increased phosphatidylinositol-3 kinase (PI3K) activity. We have determined the frequency of PIK3CA mutations in exons 9 and 20 that has previously been reported as mutational hotspot regions in distinct tumour models. One hundred and fifty gastrointestinal carcinomas (47 gastric and 103 colorectal) that were characterised for MSI status (76 MSI and 74 MSS) by PCR-SSCP sequencing were evaluated. We also analysed the association between PIK3CA mutations and KRAS or BRAF mutations. PIK3CA mutations in exons 9 and 20 were present in 13.6% and 10.6% of colorectal and gastric carcinomas, respectively. No differences in frequency and type of PIK3CA mutations were found between MSI and MSS colorectal carcinomas. All gastric carcinomas with PIK3CA mutations were MSI. The number of cases harbouring concomitant PIK3CA and KRAS or BRAF mutations was higher in colorectal than in gastric carcinomas (P = 0.016). In colorectal carcinoma, PIK3CA mutations occur preferentially together with activating KRAS-BRAF mutations (MSI and MSS) while in gastric carcinomas PIK3CA mutations tend to occur as isolated events (MSI).     

Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus

Mutation of PIK3CA, the gene coding for the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI3K), has been reported in a limited range of human tumors. We now report that PIK3CA is also mutated in esophageal tumors. Single-strand conformational polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) were used to screen all 20 exons of PIK3CA in 101 samples from 95 individuals with esophageal cancer and/or Barrett's esophagus. Somatic mutation of PIK3CA was detected in 4 of 35 (11.8%) of esophageal squamous cell carcinomas (SCC) and 3 of 50 (6%) adenocarcinomas. No mutations were detected in any of 17 samples of Barrett's esophagus. For PIK3CB, we screened exons 11 and 22, which code for the regions corresponding to the exon 9 and 20 mutational 'hotspots' of PIK3CA. No somatic changes were detected in PIK3CB This study extends previous observations in other tumor types by demonstrating the presence of somatic PIK3CA mutations in both SCC and adenocarcinoma of the esophagus, thus implicating the PI3K pathway in the initiation and/or progression of esophageal cancers.     

PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis

The implications of Phosphatidylinositol 3-kinase (PIK3CA) mutations and its aberrant protein expression in breast cancer (BC) different molecular subtypes and patients’ outcome remain controversial. The aims of this study were to assess the prevalence and clinical significance of PIK3CA protein expression in BC and to determine its association with its different molecular classes. PIK3CA protein expression was assessed in a well-characterized series of early stage BC (n = 1,394) with long-term follow-up, using tissue microarrays and immunohistochemistry. Associations between PIK3CA expression and clinicopathological variables, molecular classes, and patients’ outcome were investigated. Positive PIK3CA expression was associated with poor prognostic variables including higher grade, larger size, nodal involvement, vascular invasion, and higher proliferative fraction (P < 0.001). Increased PIK3CA expression was associated with the basal-like breast cancer (BLBC) and HER2-positive classes as well as triple negative non-basal (TNnon-B) tumors (P < 0.001). The luminal class showed reduced PIK3CA expression relative to other classes. Patients with PIK3CA positive tumors had shorter BC specific and disease free survival, independent of other prognostic factors except grade. Similar associations with outcome were found when the analysis was restricted to the large luminal class of tumors. PIK3CA is an oncogenic biomarker associated with poor prognosis in BC. Although, PIK3CA over-expression was more prevalent in BLBC and HER2-positive tumors it appeared to be a marker of poor differentiation rather than of a particular subtype. Thus, targeting of PIK3CA using specific inhibitors could potentially be beneficial, particularly for patients with more aggressive poorly differentiated tumors, irrespective of their molecular subtype.     

PIK3CA as an oncogene in cervical cancer

Amplification of chromosome arm 3q is the most consistent aberration in cervical cancer, and is implicated in the progression of dysplastic uterine cervical cells into invasive cancer. The present study employed the 'positional candidate gene' strategy to determine the contribution of PIK3CA, which is located in 3q26.3, in cervical tumorigenesis. PIK3CA is known to be involved in the PI 3-kinase/AKT signaling pathway, which plays an important role in regulating cell growth and apoptosis. The results of comparative genomic hybridization show that the 3q26.3 amplification was the most consistent chromosomal aberration in primary tissues of cervical carcinoma, and a positive correlation between an increased copy number of PIK3CA (detected by competitive PCR) and 3q26.3 amplification was found in tumor tissues and in cervical cancer cell lines. In cervical cancer cell lines harboring amplified PIK3CA, the expression of gene product (p110alpha) of PIK3CA was increased, and was subsequently associated with high kinase activity. In addition, transformation phenotypes in these lines, including increased cell growth and decreased apoptosis, were found to be significantly affected by the treatment of specific PI 3-kinase inhibitor, suggesting that increased expression of PIK3CA in cervical cancer may result in promoting cell proliferation and reducing apoptosis. These evidences support that PIK3CA is an oncogene in cervical cancer and PIK3CA amplification may be linked to cervical tumorigenesis. Oncogene (2000).