Aviel-Ronen Sarit, Coe Bradley P, Lau Suzanne K, da Cunha Santos Gilda, Zhu Chang-Qi, Strumpf Dan, Jurisica Igor, Lam Wan L, Tsao Ming-Sound
University Health Network, Ontario Cancer Institute and Princess Margaret Hospital Site, Toronto, ON, Canada.
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10155-60. doi: 10.1073/pnas.0709618105. Epub 2008 Jul 15.
Bronchioloalveolar carcinoma (BAC), a subtype of lung adenocarcinoma (ADC) without stromal, vascular, or pleural invasion, is considered an in situ tumor with a 100% survival rate. However, the histological criteria for invasion remain controversial. BAC-like areas may accompany otherwise invasive adenocarcinoma, referred to as mixed type adenocarcinoma with BAC features (AWBF). AWBF are considered to evolve from BAC, representing a paradigm for malignant progression in ADC. However, the supporting molecular evidence remains forthcoming. Here, we have studied the genomic changes of BAC and AWBF by array comparative genomic hybridization (CGH). We used submegabase-resolution tiling set array CGH to compare the genomic profiles of 14 BAC or BAC with focal area suspicious for invasion with those of 15 AWBF. Threshold-filtering and frequency-scoring analysis found that genomic profiles of noninvasive and focally invasive BAC are indistinguishable and show fewer aberrations than tumor cells in BAC-like areas of AWBF. These aberrations occurred mainly at the subtelomeric chromosomal regions. Increased genomic alterations were noted between BAC-like and invasive areas of AWBF. We identified 113 genes that best differentiated BAC from AWBF and were considered candidate marker genes for tumor invasion and progression. Correlative gene expression analyses demonstrated a high percentage of them to be poor prognosis markers in early stage ADC. Quantitative PCR also validated the amplification and overexpression of PDCD6 and TERT on chromosome 5p and the prognostic significance of PDCD6 in early stage ADC patients. We identified candidate genes that may be responsible for and are potential markers for malignant progression in AWBF.
细支气管肺泡癌（BAC）是肺腺癌（ADC）的一种亚型，无基质、血管或胸膜侵犯，被认为是一种原位肿瘤，生存率为100%。然而，侵袭的组织学标准仍存在争议。BAC样区域可能伴随其他侵袭性腺癌，称为具有BAC特征的混合型腺癌（AWBF）。AWBF被认为是由BAC演变而来，代表了ADC恶性进展的一种模式。然而，支持这一观点的分子证据仍有待进一步研究。在此，我们通过阵列比较基因组杂交（CGH）研究了BAC和AWBF的基因组变化。我们使用亚兆碱基分辨率的平铺集阵列CGH，比较了14例BAC或有局灶性可疑侵袭区域的BAC与15例AWBF的基因组图谱。阈值过滤和频率评分分析发现，非侵袭性和局灶性侵袭性BAC的基因组图谱难以区分，且与AWBF的BAC样区域中的肿瘤细胞相比，其畸变较少。这些畸变主要发生在染色体的亚端粒区域。在AWBF的BAC样区域和侵袭区域之间，观察到基因组改变增加。我们鉴定出113个能最好地区分BAC和AWBF的基因，这些基因被认为是肿瘤侵袭和进展的候选标记基因。相关基因表达分析表明，其中很大一部分基因是早期ADC患者预后不良的标志物。定量PCR也验证了5号染色体上PDCD6和TERT的扩增和过表达以及PDCD6在早期ADC患者中的预后意义。我们鉴定出了可能与AWBF恶性进展相关并可作为其潜在标志物的候选基因。
