LIEN QUAN GI0A BIEU HIEN TICH TU PROTEIN P53 y6l MOT SO YEU TO TIEN LI/0NG TRONG CARCINOM TUYEN DAI
TRIJC TRANG
Hiia Thi Ngoc Ha*, N g u y i n T h d n h N a m * *
* Bg mon Giai Phlu Benh - Dai hpc Y Dugc TP. HCM
** Trung Tam Phap Y - linh Kien Giang.
TOM T A T
Muc tieu: Xac dinh moi lien quan giOa bieu hien tich lu qua mtfc protein p53 frong UTDTT vdi mot s^ yeu to tien lUdng kh^c nhU loai mo hoc, do mo hpc. giai doan Dukes, linh Uang xam lan mach m^u, hach bach huy^t, di can hach,. .
Phtftftig phap: Mo t i cat ngang. Doi tUdng nghien cihi gdm 106 tnrdng hdp carcindm luyen dai trUc Uang dUdc chan doan va nhupm HMMD vdi p53 tai Bo mon Gidi phSu benh Dai hoc Y diroc Tp.HCM tir ihang 10/2008 den ihang 4/2009.
Kd't qua: Tuoi mac benh trung hlnh 58,08, b?nh nhSn sau 40 tu6i chi^m 91,5%. Loai mo hpc:
Carcindm hiyen khong che nhay chiem 86,8%, carcinom tuyen che nhay chiem 13,2%. Do mfi hoc: Grad 1 (8,S%), grad 2 (62,9%), grad 3 (21%), grad 4 (7,6%). Do xam l^n: Nhdm it xam l§:n chi^m 23,6%, xam lifn nhi^u (76,4%). Giai doan benh. Dukes A B, C, D lan lUdt l i 18,9%, 53,8%, 25,5% vd 1,9%. Di can hach 27,4%. Xam nhap mach mau: 18,9%. XSm nh|p mach lympho: 51,9%.Ty 16 bieu hien tich lu qua miJc protein p53 bkng HMMD la .'>0%. Lifin quan khdng cd y nghia th^ng ke giO'a bi^u hifin deh Iu protein p53 trong UTDTT vdi tudi, vi ui u, dp mo hoc, dp xSm lan, giai doan Dukes, di can hach vd xSm nhap mach lymph6. Lifin quan cd S nghia thong ke giiJa bieu hien tich tu protein p53 vdi loai md hoc, iinh Uang xam nhap mach mau.
DAT VAN DE
Ung thu dai trUc trang (UTDTT) la mdl benh thrfctng gap d ca hai gidi. Bdi vi c6 tdi 5%
dan so se bi UTDTT nen nd dUdc xem la rapt van de sdc khoe hang diu [IJ. Carcinom dai Iri/c frang la ung thU pho bien chiem hang lhi? ba frong cac loai ung thU, la nguyfin nhan gay chel
du'ng hang ihtf hai sau ung thU phoi [8]
Da CO ra't nhieu cong frinh nghien ciJu ve nhieu khia canh khdc nhau cua UTDTT tir cdc trieu chdng lam sang dfi'n hinh anh hpc va each dieu tri. Cac nghien cifu ve phan tu" giilp hieu ro them v l cd che sinh benh hoc, cai thien cac pbUdag phap chan doan va dieu tri n h l m phat hien sdm, dieu tri sdm lam giam ty le mic va ty le nV vong ciing nhiT gidp keo dai ihdi gian song Ihem.
Cdc yeu to lien liTdng kha nang song con doi vdi UTDTT gom cd: Tudi mac benh, vi fri u, loai mo hoc, do mo hoc. tinh trang t i c rudt, ihiing ruot, tinh trang xdm lan cdc lang xung quanh, xam l^n mach mdu, hach bach huyet, di cin xa,... [8]. Nhieu nghien ctfu cho thay mdi lifin he manh me giu'a mtfc do tich tu cua proieiu p53 va tien lUdng xau. NhUng cung cd mot so nghien ctfu khac cho kei qua ngUdc lai [8].
Trong ntfdc mdi cd moi cong tiinh ngliien ctfu d phia Bac ve bieu hien ciia cac khang nguyen p53, Ki-67 va Her-2/Neu frong UTDTT bing hda mo m i l n djch [25]. O phia Nam cung cd m6l cong ttinh nghien ctfu bieu hien p53, Ki-67 va Her-2/Neu Irong img thtf vu [16] va mot cong frinh nghien cihi dot bi^a gen p53 tten ung thtf mieng bing phtfdng phap PCR [17], chua cd cong trinh n i o nghi€n ctfu ve p53 tren UTDTT. Vi the chtfng loi thtfc hien de lai nay vdi muc tieu xac dinh moi liSn quan gitfa bieu hien tich Iu qua mtfc protein p53 ttong UTDTT vdi m6t s6 y^u id lien Itfdng khdc nhtf loai md hoc, do md boc, giai doan Dukes, Iinh frang xam lan mach mau, hach bach huyet. di cdn hach,....
VAT LifeU ^ P H U ( 5 N G PHAP NGHIEN CU'U
V | l lieu nghidn ctfu: 106 Irtfdng hdp carcindm tuy^n dai trtfc ttSng dtfdc chan dodn va nhupm HMMD vdi p53 tai B6 mon Giai phlu benh Dai hoc Y dtfdc Tp.HCM ttf thdng 10/2008 den thang 4/2009
Phtfdng phap nghien ctfu: Mo ta, cat ngang.
- Ghi nhan cac dac diem lam sang ttf phieu fra ldi kei qua giai phau benh, gom: Tudi, gidi, vitriu.
- Doc tieu ban: Khao sal cdc dac diem giai phlu benh:
+ Loai m6 hoc: Carcinom myen loai khong che nhay, carcinom tuyen loai che nhay (gom
201
carcuiom nhav va carcmom ie bao nhin) theo Ueu chuan phan Ioai cua WHO, 2000.
+ Do mo hoc- Gom biet hda ro, vtfa, kem va khong biei hda (theo phan do cua WHO, 2000).
+ Mtfc dp xam lan ciia u: Xam IS'n it (ldi ldp cd), xam lan nhieu (qua khoi Idp cd).
-1- Tinh Irang xim nhSp mach mau. mach lymphS v^ xam nhap quanh than kinh.
-I- Tinh Irang di can hach, sd hach bi di cin.
- Sau dd fren hanh nhupm HMMD tten cdc block paraffin de khao sat dac diem tich tu qud mtfc protein p53.
Ky thudt hoa mo miin dich di^c thifc hi$n:
Siia sogn lieu bdn:
- Cat mong mlu mo 3 - 5pm, dal vao lam sach cd Irdng silan;
- U lieu ban d nhiel do 56"C frong 1-2 gid ttUdc khi nhupm;
- Khtf ne'n frong xylen va sau dd cho qua cdn tuydt dd'i,
- Khtf peroxidase nSi sinh bSng dung dich H2O2 0,5% ttong methanol ttong 10 phdt;
- Rtfa tigu ban dtfdi v6i ntfdc dang chay, sau dd ngam vao dung dich TBS (Tris buffer solution).
Khdng the du^c sd dung:
Boc 16 khdng nguyen ttong 16 vi sdng, stf dung khang ih^ DO-7 cua nha san xui't DakoCytomation, vdi dp pha loang 1/25.
Ky thadi phtic hap Avidin-biotin vdi khdng ihe don ddng:
- Cho Ueu ban vao TBS, sau dd rtfa sach Itfdng TBS dtf;
- U vdi khang th^ ddn dong da pha loang frong 30-40 phut, rdi rtfa tieu ban bang TBS;
- U vdi khang the Ihtf hai cd gan biotin ttong 30 phiit, rtfa tieu ban bSng TBS;
- U vdi phtfc hdp Avidin-biotin 20 phdt, rfis lieu ban bang TBS:
- i l vdi dung dich DAB ttong 5-10 phtft;
- Rtfa ueu ban dtfdi voi ntfdc dang chay, nhupm mau ttfdng phan vdi hematoxylin, khtf ntfdc va dan lamen.
Danh gia srf bie'u hien ti'ch to qua mtfc protein p53:
Dtfa vao tile % nhan te bao bSI mau va dam do bat mau:
khoQg bai mau hoac <l07t bat mau;
bit mau nhai > 10%:
b i t mau tmng binh > 10%;
bai mau dam > 10%;
0:
I(+):
2(+):
Am tinh: 0.
Dtfdng tinh: 1 (-H), 2(-i-), 3(-h).
Xvl\ys&Mui
Sd lieu frong cdc bang thu tiiap dtfdc tdng hdp, phan tich va xtf ly bang phan mem SPSS 17.0 vdi phep ki^m chi binh phtfdng va ANOVA.
Tiiu chudn chpn mdu:
Ta't ca cdc trtfdng hdp ung thtf dai trtfc frang dtfdc ch^n dodn giai phlu benh \k carcindm tuyeii (loai khong che nhiy), carcindm nhay va carcinom le'bSo nhan.
Tieu chudn logi Irit:
Cdc Irtfdng hdp thieu Ihdng dn tten phi^u fra ldi k€^t qua giai phau benh hoac ihifl lac block.
KET QUA NGHIEN COU
Trong 106 tttfdng hdp dtfdc khao sdt. cd 49 nam va 57 ntf, Iy le nam/ntf = 1:1,16. Do tudi thtfdng gap ttf 40 de'n 79 tudi. Thap nhat la 20 tudi, cao nhat la 80 tudi. ttung binh 58,08 (±
13,6). Benh nhancd do tudi sau 40 chiem 91.5%.
U d dai ttdng phai (gom manh bang, dai trang len, dai frang goc gan va dai frang ngang) cd 31 tttfdng hdp, chi^m 29,5%. U d dai frang ttai (gdm dai frang gdc lach, dai ttdng xuong, dai frang sigma va trtfc frang) cd 74 trtfdng hdp, chiem 70,5%. Cd 1 trtfdng hdp khong xac dinh vi tri u.
Loai m6 hoc la carcinom tuy^n khong che" nhay cd 92 irtf&ng hdp, chifi'm 86,8%. Loai ch€'nhay (gom carcindm nhay va carcmom te bao nhin) cd 14 trtfdng hdp, chiem 13,2%
203
Carcmom tuyen biel hda vtfa chiem ly le cao nhai (62.3%). ke den la loai biel hda kem chiem 20.8%. xe'p thtf 3 la loai biet hda ro (9,4%). Carcinom loai khong biel hda chiem ty le tiiap nhat (7,5%)
Nhdm it xam lan (den ldp cd) gdm 25 mrdng hdp chi^m 23,6%. Nhdm xam lan nhieu (qua khoi ldp cd) gdm 81 trtfdng hdp, chiem 76.4%.
Dl cdn hach gap trong 29 Irtfdng hdp, chiem 27,4%.
Giai doan Dukes B gap nhieu nhat (51,9%), ke den la Dukes C (26,4%), tiitf 3 la Dukes A (19.8%). ft gap nhat IS giai doan Dukes D (1,9%).
Xam nhap mach mdu it gap vdi 20 tttfdng h(?p. chiem 18,9%.
Xam nhap mach lympho ngoai Idp cd gap Irong 55 tttfdng hdp, chiem 51,9%.
Ty lp p53 dtfdng tinh la 50%. Trong dd dtfdng linh 3(+) chie'm ly lp cao nhat vdi 26 trtfdng hdp (chie'm 24.5%). ke dd la 2(-h) vdi 14 tttfdng hdp (chiem 13,2%), sau ciing la 1(+) vdi 13 frirdng hdp (chiem 12,3%).
Bie'u hipn p53 vdi do tufi'i, vi t n u, lo^i m6 hoc, d$ mo hoc, dp xSm l^n, di cSn hach, giai doan Dukes, xSm nh^p mach mau, mach lymphd.
D3c diem
Tuoi
V i t r i
Lo^i mo hoc
Do mo h(?c
Do xam lan
</=40
> 4 0 Dai trSng phSi
Dai trang trai Khdng che nhay
ChSnhly
Grad 1 Grad 2 Grad 3 Grad 4 Xam lan it
p53 (+1 6 (66,7%) 47 (48,5%) 14(4S,16%) 38(51,35%) 50 (54,3%) 3(21,4%)
6 (60%) 35 (53%) 8 (36%) 4 (50%) 12(48%)
p53 (-) 3 (33,3%) 50(51,5%) 17 (54,84%) 36 (48,65%) 42 (45,7%) 11 (78,6%) 4 (40%) 31 (47%) 14(64%) 4 (50%) 13(52%)
P
0,29
0,56
0,022
0,51
0,81
Di can hach
Giai doan Dukes
XN mach mau
XN mach lympho
Xam lan nhieu Co Khong
A B C D Co Khong
Cd Khong
41 (50,6%) 13 (44,8%) 40 (52%) 11 (52,4%) 28 (50,1 %) 13 (46,4%) 1 (50%) 17 185%) 36 (41,8%) 27 (49%) 26(51°o)
40 i49,4°ul 16 (55,2%) 37 (48%) 10(47,6%) 27 149,9%) 15 (53,6%) 1 (50%) 3(15%) 50 (58,2%)
28(51%) 25 (49%)
0,51
0,97
0,001
0,84
Bang fren cho tiia'y bieu hien fr'ch Iu protein p53 khdc biet khdng cd ^ nghia thdng k6 vdi do tuoi. vi tri u. do mo hoc. do xam lan, di can hach, giai doan Dukes, flnh frang xam nhap mach lympho; khac biet cd y nghia tho'ng ke gitfa bieu hien tich tu protein p53 vdi loai mo hpc va Iinh frang xam nhap mach mau.
BAN LUAN
Nghien ctfu nay cho Ihay ty le p53 dtfdng tinh la 50%. Ket qua nSy phii hdp vdi cdc nghien ctftf trtfdc day, ly le p53 dtfdng tinh bang phtfdng phdp nhuom HMMD trong khoang ttf 30 den 76% [6]. [7], [9], [12], [14], [16]. [20], [23], [25].
Theo k&'t qua nghien ctfu nay, nhdm benh nhan dtfdi hay bang 40 tudi co ty le p53(-i-) cao hdn nhdm benh nhan tten 40 tudi (66,7% so \6i 48.5*7). khdc biet khong cd y nghia ihd'ng ke (p = 0,29). Kei qua nay phtf hdp vdi nhieu bdo edo khdc rang khdng cd lien quan gitfa bieu h i e n p 5 3 v d i h i d i [ 2 1 , [4], [5], [11], [13]. [27].
So sanh stf bieu hien tich lu protein p53 vdi vi ul u, nghien ctfu nay chi ra ring, p53 dtfdng tinh d dai irang ttai nhi^u hdn dai frang phai (51,35% so vdi 45.16%) Lien quan khong cd y nghia thdng ke (p = 0.56). Moi so' nghien ctfu trtfdc day cho rang khong cd hen quan cd y nghia Ihong ke gitfa bieu hien p53 va vi triu [10], [13], [19]. [23]. Nhtfng mot s d t d c gia khac
205
bdo cao ring ung Uitf 3 dai ttang trai bi^'u hien tich lu protein p53 nhieu hdn dai ttang phai [6], [21], [22]. Nhtf vay bieu hien tich tu protein p53 d ung ihtf dai trang trai cd khuynh htfdng cao hdn dai frang phai, gdi y ung Uitf dai trang ttdi lien quan den con dtfdng dot bie'n gen p53 vJ cung cd quan diem cho rdng cd stf khac biel vi 13m sdng va giai phau benh giiJa dai ttang ttdi va dai tt^ngphai.
Nghien ctfu nay cung cho thay, nhdm carcindm tuyen ch^ n h i y cho ty le p53 dtfdng tinh ra't thap (21,4%) so vdi nhdm carcinom tuyd'n khong che nhiy (54,3%), khdc bi&t cd y nghia Ihdng ke (p < 0,05). Tdc gia Georgescu [7] nghien ctftf 41 tttfdng hdp UTDTT tiia'y ring ly lp p53 dtfdng tinh bkng HMMD la 58,53%. Trong dd nhdm carcmdm tuy^n khong ch^nhay c6 65,71% p53(+), cdn nhdm carcmom tuyen chg" nhay chi cd 16,66% p53(+), stf khdc bipt cd ^ nghia Ihong ke, p < 0,05. Theo bao edo cua Ince [9], dot bie'n gen p53, phdt hifin bing giai frinh ttf gen. frong nhdm carcindm tuyS'n che' nhay it ihay hdn nhdm carcindm myd^n khdng ch^
nhay, p < 0,02. Didz [3] nghien ctfu 174 frifdng hdp UTDTT thay Iy le p53(-H) bSng HMMD Ik 477c, lien quan c6 y nghia thdng ke giffa bi^u hien tich tu protein p53 va loai md hpc.
Theo ket qua cua nghien ctfu nay, nhdm carcindm biel hda ro cd ly Ie p53 dtfdng tinh cao nh^t (60%), ke den 11 nhdm bifit hda vtfa (53%), rdi de'n nhdm khdng bifit hda (50%).
Nhdm bifit hda kfim cd ty lp p53 dtfdng tinh thap nhat (36%). Chtfng toi nhan thay Iy le p53(+) cd xu htfdng tang dan theo dp biet hda ciia ung chtf. Stf khac bipl nay khdng cd S nghia thdng ke (p = 0,51). Ket qua nay phil hdp vdi bdo edo ciia Rambau [20], p53(+) 65% d nhdm bifit hda ro. 54,3% d nhdm bifit hda vtfa va 45,5% d nhdm biet hda kfim. Ngtfdc lai, lac gia Georgescu [7] cho tii^y khuynh htfdng p53(-H) giam d i n Iheo dd bifit hda cua u. Ong nghien ctfu 41 bfinh nhan UTDTT tiiay p53(+) 33,33% d nhdm bifit hda ro, 38,46% d nhdm bifit hda vtfa va 57,14%
d nhdm biet hda kem. Cflng quan didm nay, ldc gia Trinh Tuan Dung [25] cho Ihay p53(+) 38,89% d nhdm biet hda ro, 69,23% d nhdm biet hda vtfa vk 100% d nhdm bifit hda k^m, stf khac biet cd y nghia flid'ng kfi, vdi p < 0,05. Nhilu nghifin ctfu cho thay Uch tu protein p53 khdng cd hen quan cd y nghia vdi dp mo hoc [2], [4], [5], [13], [21], [23], [27].
Nghien ctfu nay cho thify, ty Ie p53 dtfdng tinh ttong nhdm xam lan nhilu cao hdn chiit it so vdi nhdm it xam lan (50,6% so vdi 48%, p = 0,81). Nehls [15] nghien ctfu 188 tttfdng hdp
UTDTT tiiay rang i> lfi p53 dtfdng tinh d nhdm T2 52.6% ^a d nhdm T3.4 la 49.7r^ (p = 0.81i.
Theo Kandioler [ I I ] . p53 dtfdng tinh frong nhdm T2 la 69%, T3,4 la 39%. Nhtf vay, hen quan gitfa tich Iu protein p53 vdi mtfc dp xam lan khong cd -j nglua Ihdng kfi.
Trong nghifin ctfu nay, p53 dtfdng tinh frong cac tttfdng hdp cd di can hach thap hdn so vdi khong di can hach (44.8'> so vdi 52'f). Lien quan khong co y nghia thd'ng ke (p = 0.51).
Tdc gia Galizia [5] cung cho rang khdng co mdi lifin quan cd y nghia gitfa stf lich tu protein p53 va linh Irang di can hach. Cdn Iheo Didz [3], trong Id nghien ctfu 174 bfinh nhan tiii cd 43 Irtfdng hdp cd di can ttf 1-3 hach, ttong nbdm nay p53(+) 55%; 10 trtfdng hdp cd di cdn ttf 4 bach ttd len (p53(+) 71%) va 117 fri/dng hdp khdng cd di can hach (p53(+) 40%). Stf khdc bifit co y nghia thong ke. p = 0.04
Theo nghien ctftf nay. d titog giai doan benh ty le p53 dtfdng tinh vd Sm tinh ttfdng dtfdng nhau. Lien quan khdng cd y nglua thong ke (p = 0,97), Nhieu nghifin ctftf ciing cho thay khdng cd stf hen quan co y nghia giffa sif tich lu protein p53 vdi giai doan Dukes [10], [23], [271.
Kfi't qua cua nghien ctfu nay cho thay, trong nhdm cd xam nhap (XN) mach mdu. ty le p53 dtfdng tinh rat cao (85%). Trong khi dd, nhdm khong cd XN mach mdu ty le p53 dtfdng linfa la 41,86%. Lifin quan cd y nghia thdng ke (p = 0,001). Dieu nay ung hp quan diem cho rang tinh trang tich tu protein p33 cd lien quan vdi tien Itfdng xau. Theo Diez [3], stf tich tu protein p53 khong cd lien quan vdi tinh Irang XN mach mdu. Tac gia Kandioler [11] nghifin ctfu 64 benh nhan UTDTT cho tiiay ty le p53(+) bang HMMD la 45%, ty le dpt bie'n gen p53 bang giai ttinh ttf gen la 46%, tac gia thay rang khdng cd moi hen quan gitfa dpi bien gen p53 vk tinh trang XN mach mdu. Sinicrope [21] nghien ctfu 119 benh nhan UTDTT tiia'y ty le p53(+) bang HMMD la 48%. khong cd hen quan gitfa tich tu protein p53 vdi tinh ttang XN macb mdu. Nhtf vay ke't qua nghien ctfu cOa chung loi khac vdi cdc ke'l qua aky.
Theo ket qua cua chtfng toi, p53 dtfdng tinh ttong nhdm c6 XN mach lympho thap hdn chdt it so vdi nhdm khong XN macb lymphd (49% so vdi 51%). Lifin quan khdng cd y ngbia thong kfi (p = 0,66). Trong mot bdo cao kei q u i nghien ctfu 174 benh nhan UTDTT. Diez [3]
tiiS'y ning Iy lfi p53(+) bdng HMMD la 4 7 ^ . ty- lfi XN mach lymphd la 47.7%. p53(+) ttong
207
nhdm cd X.\" mach lymphd la 60% vk Irong nhdm khong cd XN mach lymphd la 51%. khdc biel khdng cd y nghia thdng kfi (p = 0,20). Kandioler [11] cung cho rang khdng cd mdi hen quan gitfa tich Iu protein p53 va tinh trang XN mach lymphd.
KET LUAN
Qua nghien ctfu 106 tttfdng hdp carcinom tuye'n dai frtfc ttang. chdng tdi nham thS'y ty lp tich tu protein p53 la 50%. Lien quan khong cd ^ nghia Ihdng ke giffa bi^u hien tich tu protein p53 frong UTDTT vdi tudi, vi tri u, dO mo hoc, do x3m lan, di can hach, giai doan Dukes va tinh frang xam nhap mach lymphd. Lifin quan cd y nghia ihd'ng kfi giffa bieu hien tich lu protein p53 vdi loai md hpc vk tinh ttang xam nhap mach mdu.
TAI LIEU THAM KHAO
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