Fracchiolla N S, Pignataro L, Capaccio P, Trecca D, Boletini A, Ottaviani A, Polli E, Maiolo A T, Neri A
Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Universita di Milano, Ospedale, Maggiore, Milan, Italy.
Cancer. 1995 Mar 15;75(6):1292-301. doi: 10.1002/1097-0142(19950315)75:6<1292::aid-cncr2820750611>3.0.co;2-b.
To understand the molecular pathogenesis of laryngeal squamous cell carcinomas (LSCCs), this study investigated the involvement of various protooncogene loci (bcl-1, int-2, c-erbB-1, c-myc, ras) and the p53 tumor suppressor gene in 18 patients with LSCC (15 at clinical presentation, 3 in clinical relapse).
For all patients, the mutations affecting the p53 and the H-, K-, and N-ras genes were evaluated by polymerase chain reaction (PCR), single-strand conformation polymorphism, and the direct sequencing of PCR-amplified fragments. The bcl-1, int-2, c-erbB-1, and c-myc loci of 15 patients were investigated using Southern blot analysis.
A mutation of the p53 gene was detected in 5/18 patients (approximately 28%), bcl-1 locus amplification in 4/15 (approximately 26%), c-erbB-1 locus amplification in 2/15 (approximately 13%), and c-myc locus amplification in 1/15 (approximately 6%). The simultaneous presence of more than one genetic lesion was observed in four patients; two showed int-2/bcl-1 coamplification, and two int-2/c-erbB-1 coamplification, one of whom also showed a p53 gene mutation. A novel p53 mutation involving the splice acceptor site of exon 6 was detected in one patient. Two of the five patients positive for p53 mutations had clinical relapses of primary tumors. bcl-1 locus amplification only was observed in patients with lymph node metastases (4/6). All but one of the patients with molecular genetic lesions showed a peculiar infiltrating pattern.
Overall, these results show that alterations of known protooncogenes and the p53 tumor suppressor gene are involved in a large proportion of LSCCs (11/18; approximately 60%) and may suggest that distinct molecular pathways occur in the pathogenesis of these tumors.
为了解喉鳞状细胞癌（LSCC）的分子发病机制，本研究调查了18例LSCC患者（15例为初诊患者，3例为临床复发患者）中各种原癌基因位点（bcl-1、int-2、c-erbB-1、c-myc、ras）及p53肿瘤抑制基因的情况。
对所有患者，通过聚合酶链反应（PCR）、单链构象多态性分析及PCR扩增片段直接测序评估影响p53及H-、K-、N-ras基因的突变情况。采用Southern印迹分析对15例患者的bcl-1、int-2、c-erbB-1及c-myc基因位点进行研究。
在18例患者中有5例（约28%）检测到p53基因突变，15例中有4例（约26%）存在bcl-1基因位点扩增，2例（约13%）存在c-erbB-1基因位点扩增，1例（约6%）存在c-myc基因位点扩增。4例患者同时存在不止一种基因病变；2例显示int-2/bcl-1共同扩增，2例显示int-2/c-erbB-1共同扩增，其中1例还存在p53基因突变。1例患者检测到一种涉及外显子6剪接受体位点的新型p53突变。5例p53基因突变阳性患者中有2例出现原发性肿瘤临床复发。仅在有淋巴结转移的患者中观察到bcl-1基因位点扩增（4/6）。除1例患者外，所有存在分子遗传学病变的患者均表现出一种特殊的浸润模式。
总体而言，这些结果表明已知原癌基因和p53肿瘤抑制基因的改变在很大比例的LSCC中存在（11/18；约60%），这可能提示这些肿瘤在发病机制中存在不同的分子途径。
