Chromosomal radiosensitivity in young cancer patients: possible evidence of genetic predisposition.

PURPOSE: To investigate the G2 chromosomal radiosensitivity of patients with cancers diagnosed when the patients are less than 20 years of age. Earlier studies demonstrated an enhanced sensitivity in substantial proportions of patients with breast or colorectal cancer, and in early onset head and neck cancer cases. Heritability of chromosomal radiosensitivity in families of breast cancer patients was also demonstrated. It is suggested that elevated sensitivity in this assay could be a marker of genetic predisposition to cancer, mediated through inherited genetic determinants of low penetrance. MATERIALS AND METHODS: Stimulated lymphocytes were exposed to 0.5 Gy X-rays in the G2-phase of the cell cycle and chromatid aberrations were scored in metaphase cells. RESULTS: The assay was performed on 32 patients with early onset cancers (aged 0.5-19 years) of various types and their sensitivity was compared with that of 41 young normal controls (0.25-19 years) and 32 adult normals (20-60 years). The proportion of cases showing enhanced sensitivity in the three groups was 44, 15 and 10%, respectively. The difference between the young patients and normals was highly significant (p = 0.004). CONCLUSIONS: The results suggest the possibility that a substantial proportion of early onset cancers are associated with the inheritance of predisposing genes of low penetrance. However, support for this hypothesis requires that the heritability of chromosomal radiosensitivity be demonstrated in family members. In addition, a larger study is now required to investigate the chromosomal radiosensitivity of specific early onset cancers.

Chromosomal radiosensitivity as a marker of predisposition to common cancers?

We previously found that 40% of breast cancer patients showed enhanced sensitivity to X-ray induced chromosome damage in G(2)lymphocytes and suggested that this might indicate a low penetrance predisposition to breast cancer, for which there is good epidemiological evidence. We have now tested the hypothesis that elevated G(2)radiosensitivity is a marker of such predisposition to other common cancers. We tested patients with colorectal cancer, for which there is also good epidemiological evidence of inherited risk in a substantial proportion of cases, and patients with cancers having a strong environmental aetiology (lung and cervix). We also repeated our study of breast cancer cases and tested patients with chronic diseases other than cancer. The results support our hypothesis, in that 30% (12/37) of colorectal cases showed enhanced sensitivity compared with 9% (6/66) of normal healthy controls (P = 0.01), whereas the proportions of sensitive cervix (11%, 3/27, P = 0.72) and lung cancer cases (23%, 8/35, P = 0.07) were not significantly above normals. We confirmed the enhanced sensitivity of 40% (12/31, P = 0.001) of breast cancer patients and found that patients with non-malignant disease had a normal response in the assay (12%, 4/34, P = 0.73). We suggest that enhanced G(2)chromosomal radiosensitivity is a consequence of inherited defects in the ability of cells to process DNA damage from endogenous or exogenous sources, of a type that is mimicked by ionizing radiation, and that such defects predispose to breast and colorectal cancer.

Retreatment of patients with intracranial gliomas by external beam radiotherapy and cytotoxic chemotherapy.

Twenty-one patients with recurrent intracranial gliomas were retreated by external beam radiotherapy between 1987 and 1995. Twenty patients received cytotoxic chemotherapy involving CCNU as part of their retreatment. Only five of the 21 patients had received chemotherapy in combination with the initial external beam radiotherapy (RT) prior to recurrence. The different histological groups were analysed and the patients divided into two groups; group I (Grade I and II gliomas) and group II (Grade III, IV and glioblastoma). The overall median survival for all patients was 59 months, with a median survival of 22 months after recurrence. For group I and group II patients, the median survival was 26 months and 13 months after recurrence respectively. It was concluded that some highly selected patients with intracranial gliomas can be retreated safely by carefully planned external beam RT given to a relatively low dose in order to palliate neurological dysfunction and the symptoms of raised intracranial pressure, and to reduce steroid dependency. The results strongly suggest that recovery does occur after initial RT. Retreatment may possibly improve survival in a small proportion of patients. Further studies, including randomized trial designs, quality of life assessment, and neurological symptoms indices, would be required to determine the quantitative benefit of any such treatment policy. The objectives of this study were to determine whether patients received any benefit, such as symptom relief and the allowance of steroid withdrawal, after retreatment, and whether long term survival could be achieved.