Molecular biological analysis of oral multiple tumor and multiple precancer

头颈部鳞状细胞癌患者多发原发肿瘤已成为临床治疗决策中越来越重要的因素。目前，临床和组织学参数用于确定是否存在多发原发肿瘤。最近的研究表明，许多上消化道多发原发肿瘤具有共同的克隆起源，挑战了长期存在的多克隆起源概念。为了确定多种口腔癌和癌前病变之间的遗传关系，我们分析了26名日本患者的100个病变。病变的发展是同步的和异时的。我们使用3pl4、9p21和17pl3染色体上的7个标记寻找微卫星改变的模式，这些微卫星改变发生在口腔癌发生的早期。在3p14、9p21和17p13的信息性多发性口腔癌和癌前病变中，分别有52.6%（41/78）、62.53%（60/96）和59.3%（32/54）发现杂合性缺失。在3p14、9p21和17pl3标记处，分别有11%、26%和13%的样品存在微卫星不稳定性。22例最初表现为非侵入性病变的患者中4例（18%）的63个病变中只有9例（14%）的微卫星改变模式是一致的。而侵袭性癌为索引病变的4例患者中，有2例在37例病变中出现16例（43%）克隆相关多发性口腔癌及癌前病变（P=0.003）。结果表明，大多数多发性口腔癌和癌前病变是由受野癌影响的克隆独立细胞引起的。然而，随着恶性进展，克隆性恶性或癌前细胞粘膜扩散的可能性可能增加。

Multiple primary tumors in patients with head and neck squamous cell carcinoma has become an increasingly important factor in clinical treatment decision. Currently, clinical and histologic parameters are used to determine whether or not multiple primary tumor is present Recent studies suggest that many multiple primary tumors in the upper aerodigestive tract have a common clonal origin, challenging the longstanding multiclonal origin concept. To determine genetic relationships among multiple oral cancerous and precancerous lesions, we analysed 100 lesions from 26 Japanese patients. Lesion development was synchronous and metachronous. We looked for patterns of microsatellite alterations using seven markers at chromosomes 3pl4, 9p21, and 17pl3, where microsatellite alteration occurs early in oral carcinogenesis. Loss of heterozygosity was found in 52.6%(41/78), 62.53% (60/96), and 59.3% (32/54) of informative multiple oral cancerous and precancerous lesions at 3p14, 9p21, and 17p13, respectively. Microsatellite instability was observed in 11, 26 and 13% of the samples at 3p14, 9p21, and 17pl3 markers, respectively. Patterns of microsatellite alterations were concordant in only nine (14%) of 63 lesions from four (18%) of 22 patients who initially presented with noninvasive lesions. However, two of four patients with invasive cancer as indexed lesion showed 16 (43%) clonally related multiple oral cancerous and precancerous lesions among 37 lesions (P=0.003). The results suggest that the majority of multiple oral cancerous and precancerous lesions arise from clonally independent cells affected by field cancerization. However, the probability of mucosal spread of clonal malignant or premalignant cells may increase along with malignant progression.