基因分型在乳腺癌个体治疗中的应用——陈振东

1、 陈振东 李 敏 陈 娟安徽医科大学第一附属医院肿瘤内科 分子病理学已经鉴别出的癌基因与抑癌基因数量众多l缺氧诱导因子-1(hypoxia inducible factor-1，hif-1)l同源盒基因(growth arrestspecific homeobox，gax)l高雌激素应答者-2 (high estrogen responders-2，her-2)l转移抑制基因(non-metastatic gene，nm23)l环化素e (cyclin e)lsurvivinlcmyc（ cmyc和her2同时表达者，赫塞停疗效更好）l血管内皮抑素(endostain，es)l血管内皮细胞生长

2、因子(vegf)ltop2a（ her-2、top2a同时扩增，蒽环类抗生素为主的化疗效果最好）lher, brca1, brca2, p53, (er, pr)找出某一肿瘤相对的专属基因并且对临床工作有所帮助相当困难。乳腺癌基因分型的参照标志lerl雌激素调节蛋白ltp53 (肿瘤蛋白p53，别名：p53基因表达物) lerbb2 l角蛋白 l层黏连蛋白l脂肪酸结合蛋白lbrca 乳腺癌基因分型的历史根据与对照乳腺组织基因表型的类似性发现，乳腺癌基因分型：:5个基因亚型有各自的特征- luminal a型c-erb-2c-erb-2、ck5/6ck5/6、egfregfr阴性阴性5个基因亚型

3、有各自的特征- luminal b型、c-erb-2c-erb-2ck5/6ck5/6、egfregfr阴性阴性5个基因亚型有各自的特征- basal-like型5个基因亚型有各自的特征- erbb2+ 型5个基因亚型有各自的特征- normal breast-like型l也写为normal-like型l高表达脂肪组织及非上皮细胞的基因，并强表达基底上皮基因，低表达腔上皮基因。l对化疗最不敏感但预后较好。l问题：以反应率为主要指标的临床研究有多大价值？基因分型试剂盒根据被检基因的数目不同，目前有：基因表达谱-21()基因表达谱-21() 乳腺癌各基因亚型的蛋白质表达 luminal a lum

4、inal b basal like erbb2 null luminal a luminal b basal like erbb2 nuller + + - - -er + + - - -pr + + - - -pr + + - - -c-erb-2 - + - + -c-erb-2 - + - + -ck5/6 - - + - -ck5/6 - - + - -egfr - - + - -egfr - - + - -l区别不同基因亚型l更好地反映肿瘤的生物学行为l预测早期乳腺癌诊断后10年内复发转移风险l筛选出适合三苯氧胺治疗者和化疗可能获益的病人，约25%的早期乳腺癌病人可因此避免接受不必要

5、的化疗 反映肿瘤的生物学行为 反映肿瘤的生物学行为预测早期乳腺癌的复发转移风险筛选适合三苯氧胺治疗者和化疗可能获益的病人 筛选适合三苯氧胺治疗者和化疗可能获益的病人筛选适合三苯氧胺治疗者和化疗可能获益的病人 筛选适合三苯氧胺治疗者和化疗可能获益的病人 brcalbrca breast cancer susceptibility gene 乳腺癌易感基因 breast cancer susceptibility protein乳腺癌易感蛋白l约510的乳腺癌有遗传易感性。l3040的家族性乳腺癌由brca基因突变引起。lbrca相关乳腺癌发病年龄提前，导管原位癌和小叶原位癌较少见，er、pr和c

6、-erb b-2基因低表达，肿瘤病理分级高，增殖抗原ki-67的表达增加brca突变：发病风险l39岁前发生乳腺癌的风险达18，l4049岁发生风险达59，l70岁前的终身风险达65。l80岁前乳腺癌发生风险为90。问题： evans dg, howell a. breast cancer risk-assessment models.breast cancer res. 2007;9(5):213. management of brca1 or brca2 carrierslintensive screening,lchemoprevention,lprophylactic surgery.

7、who should be referred for counseling and tested for brca1 and brca2 mutations?lbreast cancer40 yr oldlat least two instances of breast cancer 50 yr oldlovarian cancer and breast cancer in the same lineage (breast 50 or 2 cases of breast cancer)lmale breast cancer (if close relative has breast or ov

8、arian cancer)lmore than three cases with breast cancer in the same lineagelrelatives of known brca1 or brca2 carrier基因检测的潜在影响 阳性(基因突变)检测结果基因检测及普查的潜在影响 阴性(无基因突变)检测结果化学预防 calderonmargalit r，paltiel o prevention of breas t cancer in women who carry brca1 an d brca2 mutationsa critical review of the lit

9、eratureint j cancer，2004，ll2(3)：357-364lbrca1 carriers tend to develop er - tumors，tamoxifen had about a 40% reduction in their risk of contralateral breast cancer. metcalfe ka, lynch ht, ghadirian p, et al. the risk of ovarian cancer after breast cancer in brca1 and brca2 carriers. gynecol oncol. 2

10、005; 96:222-226.lno data on the role of aromatase inhibitors in mutation carriers.手术预防 rebbeck tr，friebel t，lynch ht，et a1bilateral prophylactic mastectomy reduces breast cancer risk in brcal and brca2 mutation carriers：the prose study groupclin oncol，2004，22(6)：lo55-1o62 保乳术的风险 robson mis breast co

11、nservation a reasonable option for women with brca associated breast cancer?nat clin pract oncol，2007，4(1)：10-11。 metcalfe k，lynch ht，ghadirian p，et a1contralateral breast caneer in brcal and brca2 mutation carriersj clin oncol，2004，22(12)：23282335 brca相关乳腺癌引发的问题brca1l定位于定位于17q2117q21以染色体显性方式遗传，外以染色

12、体显性方式遗传，外显率在乳腺癌为显率在乳腺癌为60608080，卵巢癌也可，卵巢癌也可达达15154040。l家族性乳腺癌中家族性乳腺癌中brca1brca1基因突变率为基因突变率为20203030；4545岁的家族性乳腺癌患者中，突岁的家族性乳腺癌患者中，突变率可达变率可达7070；3535岁的散发性病例中，岁的散发性病例中，突变率为突变率为1010；在整个乳腺癌人群中，估；在整个乳腺癌人群中，估计为计为3 3左右。左右。brca1相关乳腺癌 gofin jr，et a1impact of germline brca1 mutations and overexpression of p53

13、on prognosis and response to treatment following breast carcinoma：10 year follow-up datacancer，2003，97(3)：527536brca2l定位于定位于13q1213q12lbreast cancers in brca2 carriers are frequently er positive and are not significantly different in appearance from sporadic disease. lbreast cancers in brca1 carrier

14、s are more frequently er negative, have more aggressive appearing histology, and commonly have a basaloid phenotype. foulkes wd, stefansson im, chappuis po, et al. germline brca1 mutations and a basal epithelial phenotype in breast cancer. j natl cancer inst. 2003;95:1482-1485.ldespite the more aggressive phenotype of these cancers, it is not yet apparent if brca1 status is an independent adverse prognostic feature. lgiven the relative paucity of data, at present brca status should not impact systemic treatment decisions.l35岁， brca1/2突变，保乳相对禁忌证。nccn,