SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit
SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit
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DOI：
10.1002/path.2464
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发表时间：
2009-02-01
影响因子：
7.3
通讯作者：
Panda, Chinmay K.
中科院分区：
文献类型：
--
作者：
Ghosh, Amlan;Ghosh, Susmita;Panda, Chinmay K.
为了了解候选抑癌基因 SH3GL2、p16(INK4a)、p14(ARF) 和 p15(INK4b) 在头颈鳞状细胞癌 (HNSCC) 发病机制中的关联，我们研究了 61 个不典型增生病变和 94 个 HNSCC 样本中这些基因的缺失、突变和甲基化情况。在轻度不典型增生中，SH3GL2、p16(INK4a) 和 p14(ARF) 表现出比 p15(INK4b) (40%) 更高的总体改变频率 (60-70%)。然而，在肿瘤进展的后续阶段，这些基因的改变频率并没有显着变化。在 p16(INK4a)/p14(ARF) 的共同外显子 2 中发现了一个新突变，在 SH3GL2 的外显子 9 中发现了三个新突变。这些基因的表达与其分子改变具有一致性。 INK4A-ARF 和 p15(INK4b) 的缺失会导致患者预后显着较差。 p16(INK4a)、P14(ARF)和p15(INK4b)的改变与烟草呈正相关，与HPV呈负相关，而SH3GL2的改变与这些因素无关。根据病因学因素，确定了四种肿瘤亚型：HPV(-)烟草(-) (I)、HPV(+)烟草(-) (II)、HPV(-)烟草(+) (III)和HPV(+)烟草(+) (IV)。与 II 组相比，III 组和 TV 组显示出高频率的 p16(INK4a)/P14(ARF)/p15(INK4b) 改变，患者预后显着较差。我们的研究结果表明，SH3GL2 相关信号传导的失调和 p16(INK4a)/p14(ARF)/p15(INK4b) 介导的细胞周期 G1-S/G2-M 检查点是头颈部早期发育不良病变发展的独立途径。版权所有 (C) 2008 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
To understand the association of candidate tumour suppressor genes SH3GL2, p16(INK4a), p14(ARF), and p15(INK4b) in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), we studied the deletion, mutation, and methylation of these genes in 61 dysplastic lesions and 94 HNSCC samples. In mild dysplasia, SH3GL2, p16(INK4a), and p14(ARF) showed a higher frequency of overall alterations (60-70%) than in p15(INK4b) (40%). However, in subsequent stages of tumour progression, the alteration frequency of these genes did not change significantly. One novel mutation in common exon 2 of p16(INK4a)/p14(ARF) and three in exon 9 of SH3GL2 were seen. Concordance was seen in the expression of these genes with their molecular alterations. Deletions of INK4A-ARF and p15(INK4b) have a significant poor patient outcome. The alterations of p16(INK4a), P14(ARF), and p15(INK4b) were positively correlated with tobacco and inversely with HPV, while SH3GL2 alterations were independent of these factors. Based on aetiological factors, four tumour subtypes were recognized: HPV(-)tobacco(-) (I), HPV(+)tobacco(-) (II), HPV(-)tobaccol(+) (III), and HPV(+)tobacco(+) (IV). Groups III and TV showed a high frequency of p16(INK4a)/P14(ARF)/p15(INK4b) alterations with significant poor patient outcome in comparison to group II. Our findings suggest that deregulation of SH3GL2-associated signalling and p16(INK4a)/p14(ARF)/p15(INK4b)-mediated G1-S/G2-M checkpoints of cell cycle are independent pathways for the development of early dysplastic lesions of the head and neck. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.