消化道腫瘤的遺傳學(xué)

1、1消化道腫瘤的遺傳學(xué)張咸寧（細(xì)胞生物學(xué)與醫(yī)學(xué)遺傳學(xué)系）2016/05I.I. CausesCauses ofof CancerCancerCan cer is a group of gen etic diseases affect ing fun dame ntal asp ects of cellular function, in clud ingDNA rep air, cell-cycle regulati on, apop tosis, and sig nal tran sducti on.主控基因（driverdriver genegene）是一類一旦發(fā)生突變就有可能促進(jìn)癌癥發(fā)生、發(fā)

2、展的基 因，是決定癌癥的最主要遺傳因素。如TP53基因。主控基因突變 的頻率高，且非隨機(jī)，發(fā)生于同一種癌癥的多個樣本，或不同的癌癥中。主控基因突變是腫瘤發(fā)生中的 陽性選擇結(jié)果。副控基因（PassengergenePassengergene是指那些突變后可能影響癌癥發(fā)展的基因。副控基因突變是隨機(jī)的，是腫瘤發(fā)生中的陰性選擇結(jié)果。絕大多數(shù)體細(xì)胞突變都屬于副控基因 突變，非某種癌癥所特有。一種典型的癌癥包含28個主控基因，其他的突變基因則為副控基因。TABLETABLE 15-115-1 ClassesClasses ofof DriverDriver GenesGenes MutatedMutate

3、d inin CancerCancer （癌癥的主控基因類型）GenesGenes withwith GlobalGlobal EffectsEffects onon GenomeGenome oror DNADNA IntegrityIntegrity oror onon GeneGeneExpExp ressionression（全局性維持 基因組和DNADNA的完整性、調(diào)控基因表達(dá)的主 控基因）Genome integrity（基因組完整性）?Chromosomesegregation染色體分離）?Ge nome and gene mutatiort基因組和基因突 變）?DNA rep

4、air（DNA修復(fù)）?Telomere stability（端粒的穩(wěn)定性）Gene exp ressi on: abno rmal metabolites affecti ng activity ofmult ip le gen es/ge ne products（基因表達(dá)：異常代謝物影響多個 基因或基因產(chǎn)物的活性）Gene exp ressi on: epigen etic modificatio ns of DNA/chromatin（基因表達(dá)：DNA或染色質(zhì) 的表觀修飾）?DNA methylati on and hydroxymethylati on（DNA甲基化和羥甲基化）?Chro

5、mati n hist one methylation, demethylati on, andacetylation（組蛋白甲基化、去甲基化和乙 ?；㎜ectureLecture NotesNotesGenesGenes withwith SpSp ecificecific EffectsEffects onon CellularCellularProliferationProliferation oror ApopApop tosistosis（特異性調(diào)控細(xì)胞增殖和凋亡的主控基因）Cell-cycle regulation（細(xì)胞周期的 調(diào)控）Cell-cycle check point

6、p rote ins（纟田 胞周期檢查點蛋白）Cellular p roliferati on sig nali ng胞增殖的信號通路）?Transcription factors（轉(zhuǎn)錄因子）?Receptor and membrar-fo ound tyrosine kinases（受體和膜結(jié)合的酪 氨酸激酶）?Growth factors（生長因子）?ln tracellular seri nethre onine kin ases（胞內(nèi)絲氨酸-蘇氨酸激酶）?PI3 kin ases（ PI3激酶）?G p rote ins and G p rote incoupireceptors（G蛋

7、白和G蛋白偶聯(lián)受 體）?mT0R signaling （mTOR信號通路）（細(xì)2GenesGenes withwith GlobalGlobal EffectsEffects onon GenomeGenome oror DNADNA IntegrityIntegrity oror onon GeneGeneExpExp ressionression（全局性維持 基因組和DNADNA的完整性、調(diào)控基因表達(dá)的主 控基因）?Nucleosome remodeli ng（核小體重塑）?Chromat inaccessibility and comp actio n（染色質(zhì) 的可達(dá)性和壓縮）（SWI/

8、SNF comp lexes SWI/SNF復(fù)合體） Gene exp ressi on:p ost-tra nscri pti onal alterations（基因表達(dá)：轉(zhuǎn)錄后改變）?Aberrant mRNA splicing（異常的mRNA剪 接）?MicroRNAs affecti ng mRNA stability and translation（影響mRNA穩(wěn)定性和翻譯的miRNA）Gene exp ressi on: p rotein stability/turnover（基因表達(dá)：蛋白的穩(wěn)定性和轉(zhuǎn)換）mTOR, mammalia n target of rap amyci n

9、; P13, p hos phatidylino sitol-3. SWI/SNF com plex=SWItchi ng/Sucrose Non Ferme ntable comp lex為多亞基組成的染色質(zhì)重塑復(fù)合體，屬于全局性轉(zhuǎn)錄因子，可特異性激活基因的轉(zhuǎn)錄。表癌基因與抑癌基因特點原癌基因抑癌基因基因功能正常生長和增殖必需增殖負(fù)調(diào)控，分化必需突變（激活）方式點突變、染色體重排、點突變、LOH等基因擴(kuò)增、病毒插入致癌方式（They behave顯性隱性as）突變蛋白的效應(yīng)功能失去突變功能獲得突變遺傳方式體細(xì)胞突變，不遺傳體細(xì)胞或生殖細(xì)胞突變，可遺傳常見于哪些癌腫白血病、淋巴瘤實體瘤1971

10、年，Knu dson提出了著名的“二次突變假說” （two-hit theory）,用以闡釋遺 傳型與散發(fā)型視網(wǎng)膜母細(xì)胞瘤的遺傳機(jī)制。兩種類型的腫瘤都起源于同一基因的兩次 以上的突變。遺傳型視網(wǎng)膜母細(xì)胞瘤患者的第一次突變發(fā)生于生殖細(xì)胞，使嬰兒的所 有體細(xì)胞都含有此突變，成為突變的雜合子，第二次突變則發(fā)生于同一視網(wǎng)膜體細(xì)胞 中另一個等位基因，二次突變完成腫瘤的始動，使良性細(xì)胞轉(zhuǎn)變?yōu)閻盒约?xì)胞。因此， 遺傳型病例發(fā)病早，常呈雙側(cè)與多灶性。在散發(fā)病例中，二次突變均發(fā)生在體細(xì)胞， 而且必須在同一視網(wǎng)膜母細(xì)胞中的兩個等位基因先后發(fā)生才能完成腫瘤的始動過程， 這種機(jī)會很少，需要漫長的時間積累，因而散發(fā)病例發(fā)

11、病較晚，多為單側(cè)。實際上，腫瘤的形成是一個多步驟發(fā)生的過程，涉及到多種相關(guān)基因包括癌基因和 腫瘤抑制基因GenesGenes withwith SpSp ecificecific EffectsEffects onon CellularCellularProliferationProliferation oror ApopApop tosistosis（特異性調(diào)控細(xì)胞增殖和凋亡的主控基因）?Wnt/ 3-catenin signaling（Wnt/伕cate nin信號通路）Differe ntiatio n and lin eage survival（分化和譜系的生存）?Tra nscri

12、ptio n factors p rotecti ng specificcell lineages（保護(hù)特定細(xì)胞譜 系的轉(zhuǎn)錄因子）?Ge nes invo Ived in exit from cell cycle intoGo（使細(xì)胞周期返回到Go期的基 因）Apoptosis（凋亡）3的變異。一種腫瘤會有多種基因的變化，而同一種基因的改變也會在不 同種類腫瘤的發(fā)生中起作用，大多數(shù)腫瘤的發(fā)生與癌基因的活化和腫瘤抑制基因的失 活有關(guān)。結(jié)腸癌就是腫瘤多步驟發(fā)生的最好例子。II.II. ColorectalColorectal CancerCancer （CRCCRC）1. Familial ade

13、nomatouspolyposis （FAP。家族性多發(fā)性腺癌、家族性腺瘤性息肉?。?is also calledadenomatouspolyposis coli （APC。腺瘤性息肉?。? an autosomal dominant subtype of colon cancer that ischaracterized by a large number of adenomatous polyps.2.Pen etra nee（外顯率）of FAP is virtually 100%.3.More than 700 different mutations of the APC gene

14、（5q21） have been reported, most of whieh are nonsenseor frameshift mutations.4.APC is an adhesion molecule（黏附分子）.Interacts withgcatenin and when APC is mutated, the eomplexaeeumulates in the eell leading to transeriptional aetivation of other tumor promoting genes5.Lynch syndrome （又稱hereditary nonpo

15、lyposis colorectal cancer, HNPCC。遺傳性 非息肉性結(jié)直腸癌）, an autosomal dominant high-penetrance cancer syndrome, comprises 13% of CRC and is characterized byearly-onset proximal CRC exhibiting MSI （microsatellitein stability。微衛(wèi)星不穩(wěn)定性）.6.MSI: A type of genomic instability seen in some colon and other cancers wh

16、ere replication errors arenot corrected; observed as the production of extra alleles at many polymorphic microsatellites.（微衛(wèi)星DNA是散布在基因組內(nèi)的一類重復(fù)序列，不同個 體之間有差別，在遺傳上高度保守。在一些腫瘤細(xì)胞或癌前病變細(xì)胞中發(fā)現(xiàn)微衛(wèi)星DNA的重復(fù)序列的拷貝數(shù)有變化，稱之為微衛(wèi)星不穩(wěn)定性）7.HNPCC is causedby mutations in any of six genes （MSH2, MLH1, MSH6, MLH3, P MS1 in volve

17、d in DNA mismatchrep air（DNA錯配修復(fù)）8.LOH （loss of heterozygosity。雜合性丟失）:Loss of a normal allele from a region of one chromosomeof a pair, allowing a defective allele on the homologous chromosome to be clinically manifest.（一對雜合的等位基因變成純合狀態(tài)的現(xiàn)象。往往會導(dǎo)致細(xì)胞病變）9.TP53是人體最重要的抑癌基因，被稱為“Guardia n of the geno me,在多達(dá)8

18、5%的CRC患者中可見TP53基因突變；而K-ras基因是第1個腸癌的生物標(biāo)志（biomarker） 在32%57%的患者中可見K-ras基因突變，故K-ras基因是重要的腸癌預(yù)測、預(yù)后指 標(biāo)。10. Clinical decision tree for the systematic evaluation of suspected inherited CRC syndromes:411. Epigen etics of colorectal can ce:Epigen etic p rocessesdo not in elude cha nges in DNA sequenee,but are

19、 potentially reversible genetic modifications leading to genomic in stability and malf un cti on. Theestimated loss of ep ige netic con trol may be one to two fold(s) more than that of somatic DNA mutations. Epigeneticschanges include: (1) altered DNA methylati on, (2) chromati n remodeli ng and (3)