Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy
Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy
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DOI：
10.1093/jnci/90.20.1545
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发表时间：
1998-10-21
期刊：
影响因子：
--
通讯作者：
Hong, WK
中科院分区：
文献类型：
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作者：
Mao, L;Ei-Naggar, AK;Hong, WK
背景资料：化学预防的目标是通过使用药理学或天然试剂逆转或阻断肿瘤发生过程来降低癌症发展的风险。为了确定遗传改变在评估癌症风险和评价化学预防剂的功效中的潜在作用，我们研究了22名头颈部晚期癌前病变患者，他们是一项前瞻性癌症预防试验的一部分，13-顺式-视黄酸、干扰素α和α-生育酚给药12个月或直至疾病进展。研究方法：我们使用聚合酶链反应分析癌前病变细胞中的微卫星DNA序列，以确定遗传变异的频率，即杂合性丢失（洛）和微卫星不稳定性，在染色体位点，通常删除头颈癌。结果如下：在治疗前，21例中有17例（81%）、18例中有8例（44%）和19例中有8例（42%）分别在染色体9 p21、3 p14和17 p13处有信息（即杂合子），在至少一个病变活检标本中显示出洛合性缺失。在9例治疗前活检标本中染色体9 p21处显示洛缺失且已完成至少5个月治疗的患者中，8例患者的遗传丢失持续存在，其中4例患者中有3例显示完全组织学缓解（即，活检标本中无发育异常证据）。含义：我们的数据表明，对化学预防剂的反应的临床和组织学评估可能不足以确定其疗效，并且关键的遗传改变可用作独立的生物标志物以增强评估此类药物疗效的能力。
Background: The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents, To determine the potential role of genetic alterations in assessing cancer risk and in evaluating the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen of 13-cis-retinoic acid, interferon alfa, and or-tocopherol administered for 12 months or until disease progression. Methods: We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations-namely, loss of heterozygosity (LOH) and microsatellite instability-at chromosomal loci that are commonly deleted in head and neck cancer. Results: Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i,e,, heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight-including three of the four patients who exhibited complete histologic responses (i,e,, no evidence of dysplasia in their biopsy specimens). Implication: Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents.