ERBB2, TBX2, RPS6KB1, and MYC alternations in breast tissues of BRCA1 and BRCA2 mutation carriers
ERBB2, TBX2, RPS6KB1, and MYC alternations in breast tissues of BRCA1 and BRCA2 mutation carriers
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DOI：
10.1002/gcc.20057
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发表时间：
2004-09-01
影响因子：
3.7
通讯作者：
Jenkins, RB
中科院分区：
文献类型：
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作者：
Adem, C;Soderberg, CL;Jenkins, RB
携带 BRCA1 或 BRCA2 基因突变的女性患乳腺癌的风险大大增加。由于 BRCA1/2 突变携带者和不携带突变的女性之间的乳腺癌发生不同，因此乳腺癌进展的机制也可能不同。组织病理学和遗传学研究支持了这一假设。为了进一步检验这一假设，我们利用了一大群接受了治疗性乳房切除术 (TM) 和对侧预防性乳房切除术 (PM) 的女性。从该队列中，我们开发了具有 BRCA1/2 有害突变、未分类变异改变和未检测到突变的乳腺癌家族史的女性病例组，并将这些病例与来自同一 TM 和 PM 队列的散发对照进行匹配。使用 ER882/CEP17、MYCICEP8、TBX21CEP17 和 RPS6KB1/CEP17 双色探针对石蜡切片进行荧光原位杂交。研究了所有恶性和良性病变，包括假定的前期病变。与对照相比，有害突变携带者的侵袭性癌症的 MYC (P = 0.006) 和 TBX2 (P = 0.0008) 重复发生率较高，而 ERB82 扩增发生率较低 (P = 0.011)。 MYC 和 TBX2 的共复制在有害突变携带者的原位和侵袭性病变中很常见。当 MYC 和 TBX2 共复制但 ERBB2 正常时，出现 BRCA1/2 突变的优势比为 31.4 (95% Cl = 1.7-569)。未分类的变异携带者/未检测到突变和散发性对照具有相似的改变发生率，这表明没有有害突变的遗传性患者遵循与散发性病例相似的进展途径。除了一处非典型导管增生病变外，没有假定的前体病变显示出所测试探针的任何可检测到的改变。遗传改变不存在显着的瘤内异质性。我们的数据证实，基因组不稳定的特定模式是 BRCA 1/2 相关慢跑的特征，并且这种模式对这些癌症的生物学具有影响。此外，我们当前和之前的结果强调了 BRCA 1/2 相关乳腺癌表型和基因型之间的相互作用，并且形态特征和 ERBB2、MYC 和 TBX2 改变的组合可以更好地定义肿瘤进展机制，并确定哪些患者更有可能携带 BRCA1/2 突变。 (C) 2004 Wiley-Liss, Inc.
Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ER882/CEP17, MYCICEP8, TBX21CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERB82 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% Cl = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA 1/2-related canters and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA 1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations. (C) 2004 Wiley-Liss, Inc.