Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas
Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas
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DOI：
10.1016/s0002-9440(10)64191-0
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发表时间：
2002-08-01
影响因子：
6
通讯作者：
Rao, PH
中科院分区：
文献类型：
--
作者：
Singh, B;Stoffel, A;Rao, PH
3q26-q27的扩增在粘膜源性鳞状细胞癌中有很高的患病率，包括那些起源于头颈部的鳞状细胞癌。为了阐明其作为头颈部鳞状细胞癌预后工具的作用，构建了一个横跨整个3q26-27区域的酵母人工染色体（YAC）。使用序列荧光原位杂交分析，在三个重叠的非嵌合的YAC克隆中，将最小扩增区域细化为1- 2mb基因组片段。利用含有扩增尖的YAC克隆建立双色荧光原位杂交法，并应用于29例正常黏膜、20例癌前黏膜和50例侵袭性头颈部鳞状细胞癌档案肿瘤组织间期细胞核3q拷贝数的检测。3q扩增率从正常黏膜的3%增加到癌前黏膜的25%和浸润性癌的56% （P < 0.01）。在侵袭性肿瘤中，50例原发性头颈癌中有18例发现低水平3q扩增（3 - 4倍拷贝数），50例中有10例发现高水平3q扩增（4倍拷贝数）。中位随访82.5个月，3q拷贝数正常、低水平扩增和高水平扩增的患者的复发率（32%、72%和90%，P = 0.003）和癌症相关死亡（14%、44%和70%，P = 0.006）分别增加。3年无病生存率（69%、56%和10%，P = 0.001）和病因特异性生存率（94%、83%和40%，P = 0.01）也从正常拷贝数下降到低水平和高水平扩增。在多变量分析中，只有3q的高水平扩增仍然是一个重要的预后变量，包括无病（相对风险，5.1；95%置信区间= 1.9至13-9）和病因特异性生存（相对风险，7.6；95%置信区间= 1.9至29.6）的常见预后预测因子。研究结果提示3q拷贝数状态是头颈部鳞状细胞癌患者肿瘤进展和预后的重要标志。
Amplification of the 3q26-q27 has a high prevalence in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. To elucidate its role as a prognostic tool in head and neck squamous cell carcinoma, a yeast artificial chromosome (YAC) contig spanning the entire 3q26-27 region was constructed. The minimal region of amplification was refined within a 1- to 2-Mb genomic segment contained within three overlapping, nonchimeric YAC clones using sequential fluorescent in situ hybridization analysis. These YAC clones containing the apex of amplification were used to develop a two-color fluorescence in situ hybridization assay and applied to the detection of 3q copy numbers in interphase nuclei on archival tumor tissue from 29 cases of normal mucosa, 20 of premalignant mucosa, and 50 of invasive head and neck squamous cell carcinomas. The presence of 3q amplification increased from 3% in normal mucosa to 25% in premalignant mucosa and 56% in invasive cancers (P < 0.01). In invasive tumors, low-level 3q amplification (3 to 4 X copy number) was identified in 18 of 50 primary head and neck cancers and high-level amplification (>4 X copy number) in 10 of 50 cases. With a median follow-up of 82.5 months, an increasing proportion of recurrences (32%, 72%, and 90%; P = 0.003) and cancer-related deaths (14%, 44%, and 70%; P = 0.006) were seen in patients with normal 3q copy number, low-level amplification, and high-level amplification, respectively. The 3-year disease-free (69%, 56%, and 10%; P = 0.001) and cause-specific (94%, 83%, and 40%; P = 0.01) survivals also decreased from normal copy number to low-level and high-level amplification. Only high-level amplification at 3q remained a significant prognostic variable on multivariate analysis including common prognostic predictors for both disease-free (relative risk, 5.1; 95% confidence interval = 1.9 to 13-9) and cause-specific survival (relative risk, 7.6; 95% confidence interval = 1.9 to 29.6). The findings suggest that the 3q copy number status is an important marker for tumor progression and prognostication in patients with head and neck squamous cell carcinoma.