Patocs Attila, Zhang Li, Xu Yaomin, Weber Frank, Caldes Trinidad, Mutter George L, Platzer Petra, Eng Charis
Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland 44195, USA.
N Engl J Med. 2007 Dec 20;357(25):2543-51. doi: 10.1056/NEJMoa071825.
The importance of cross-talk between a cancer and its microenvironment has been increasingly recognized. We hypothesized that mutational inactivation of the tumor-suppressor gene TP53 and genomic alterations in stromal cells of a tumor's microenvironment contribute to the clinical outcome.
We performed TP53 mutation analysis and genomewide analysis of loss of heterozygosity and allelic imbalance on DNA from isolated neoplastic epithelial and stromal cells from 43 patients with hereditary breast cancer and 175 patients with sporadic breast cancer. Compartment-specific patterns and TP53 mutations were analyzed. Associations between compartment-specific TP53 status, loss of heterozygosity or allelic imbalance, and clinical and pathological characteristics were computed.
TP53 mutations were associated with an increased loss of heterozygosity and allelic imbalance in both hereditary and sporadic breast cancers, but samples from patients with hereditary disease had more frequent mutations than did those from patients with sporadic tumors (74.4% vs. 42.3%, P=0.001). Only 1 microsatellite locus (2p25.1) in stromal cells from hereditary breast cancers was associated with mutated TP53, whereas there were 66 such loci in cells from sporadic breast cancers. Somatic TP53 mutations in stroma, but not epithelium, of sporadic breast cancers were associated with regional nodal metastases (P=0.003). A specific set of five loci linked to an increased loss of heterozygosity and allelic imbalance in the stroma of sporadic tumors was associated with nodal metastases in the absence of TP53 mutations. No associations were found between any of the clinical or pathological features of hereditary breast cancer with somatic TP53 mutations.
Stroma-specific loss of heterozygosity or allelic imbalance is associated with somatic TP53 mutations and regional lymph-node metastases in sporadic breast cancer but not in hereditary breast cancer.
肿瘤与其微环境之间的相互作用的重要性已得到越来越多的认可。我们推测肿瘤抑制基因TP53的突变失活以及肿瘤微环境中基质细胞的基因组改变会影响临床结局。
我们对43例遗传性乳腺癌患者和175例散发性乳腺癌患者的肿瘤上皮细胞和基质细胞DNA进行了TP53突变分析以及全基因组杂合性缺失和等位基因不平衡分析。分析了不同区域的特定模式和TP53突变。计算了不同区域特异性TP53状态、杂合性缺失或等位基因不平衡与临床和病理特征之间的关联。
在遗传性和散发性乳腺癌中，TP53突变均与杂合性缺失增加和等位基因不平衡相关，但遗传性疾病患者的样本比散发性肿瘤患者的样本有更频繁的突变（74.4%对42.3%，P = 0.001）。遗传性乳腺癌基质细胞中只有1个微卫星位点（2p25.1）与TP53突变相关，而散发性乳腺癌细胞中有66个这样的位点。散发性乳腺癌基质而非上皮中的体细胞TP53突变与区域淋巴结转移相关（P = 0.003）。一组特定的5个位点与散发性肿瘤基质中杂合性缺失增加和等位基因不平衡相关不平衡相关，在无TP53突变的情况下与淋巴结转移相关。遗传性乳腺癌的任何临床或病理特征与体细胞TP53突变之间均未发现关联。
散发性乳腺癌而非遗传性乳腺癌中，基质特异性杂合性缺失或等位基因不平衡与体细胞TP53突变及区域淋巴结转移相关。
