Kaminski Britta C, Grabenbauer Gerhard G, Sprung Carl N, Sauer Rolf, Distel Luitpold V R
Department of Radiation Oncology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany, and Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Eur J Cancer Prev. 2006 Jun;15(3):274-82. doi: 10.1097/01.cej.0000199502.23195.29.
Since the development of multiple primary cancers in an individual is considered an unlikely event, it is suspected that a defect in DNA repair or apoptosis is the underlying cause for some of these patients. Therefore, this study was based on the hypothesis that such patients have increased remaining DNA double-strand breaks (DSBs) and reduced levels of apoptosis after in vitro irradiation. To investigate these mechanisms in cancer patients, 19 with multiple primary cancers were selected out of 25 121 cancer patients. For inclusion in this study, patients had to present with first malignancy at an early age, have a positive family history of cancer and no risk factors. The exclusion criteria were recurrence of cancer or metastasis, haematological tumours and tumours possibly connected to a patient risk factor such as smoking or drinking. Their peripheral blood lymphocytes were tested for proper repair of DNA DSBs and apoptosis after in vitro irradiation. DSBs were measured using constant field gel electrophoresis at 0, 8 and 24 h after irradiation. Apoptotic rates were determined at 24, 48 and 72 h after irradiation using the TUNEL assay. We found that patients' lymphocytes had significantly more initial DNA DSBs compared with controls, but there was no difference in the number of remaining DNA DSBs. Apoptotic rates of lymphocytes were only slightly lower in patients than in controls. These findings show that there are limited differences between patients with multiple cancers and healthy individuals. However, we found a trend towards an inverse correlation between remaining DNA DSBs and apoptotic rates in patients' lymphocytes. This is indicative of DNA DSBs persisting in patients' cells, presumably leading to a higher level of stable chromosomal aberrations that may contribute to tumour formation.
由于个体发生多种原发性癌症被认为是不太可能的事件，因此怀疑DNA修复或细胞凋亡缺陷是其中一些患者的潜在病因。因此，本研究基于这样的假设，即这些患者在体外照射后剩余的DNA双链断裂（DSB）增加，细胞凋亡水平降低。为了研究癌症患者的这些机制，从25121名癌症患者中选出了19名患有多种原发性癌症的患者。纳入本研究的患者必须在早年出现首例恶性肿瘤，有癌症家族史且无危险因素。排除标准为癌症复发或转移、血液系统肿瘤以及可能与吸烟或饮酒等患者危险因素相关的肿瘤。对他们的外周血淋巴细胞进行体外照射后DNA DSB的正确修复和细胞凋亡检测。照射后0、8和24小时使用恒定电场凝胶电泳测量DSB。照射后24、48和72小时使用TUNEL法测定凋亡率。我们发现，与对照组相比，患者的淋巴细胞初始DNA DSB明显更多，但剩余DNA DSB的数量没有差异。患者淋巴细胞的凋亡率仅略低于对照组。这些发现表明，患有多种癌症的患者与健康个体之间的差异有限。然而，我们发现患者淋巴细胞中剩余的DNA DSB与凋亡率之间存在负相关趋势。这表明DNA DSB在患者细胞中持续存在，可能导致更高水平的稳定染色体畸变，这可能有助于肿瘤形成。
