Inter-relation of apoptosis and DNA double-strand breaks in patients with multiple primary cancers.

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.