Investigation of G2-phase chromosomal radiosensitivity in hereditary non-polyposis colorectal cancer cells

• Published in: International journal of radiation biology Vol. 77; no. 7; pp. 773 - 780
• Main Author: Franchitto, P. Pichierri, M. Genuardi, A. De Santis, F. Palitti, A.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 2001; Taylor & Francis
• Subjects: Adaptor Proteins, Signal Transducing; Alleles; Base Pair Mismatch; Biological and medical sciences; Biological effects of radiation; Bromodeoxyuridine - metabolism; Carrier Proteins; Chromosomes - radiation effects; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - radiotherapy; Diseases of the digestive system; DNA Repair; DNA-Binding Proteins; Fundamental and applied biological sciences. Psychology; G2 Phase - radiation effects; Genetic Predisposition to Disease; Heterozygote; Humans; Ionizing radiations; Loss of Heterozygosity; Medical sciences; Mutation; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins - genetics; Nuclear Proteins; Proto-Oncogene Proteins - genetics; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Time Factors; Tissues, organs and organisms biophysics; Tumor Cells, Cultured; X-Rays; Chromosomal aberration; Human; Cell culture; Evaluation; Rectal disease; Radiosensitivity; Case control study; Malignant tumor; Genetic determinism; X ray irradiation; Heterozygosity; Colonic disease; Rectum; G2 Phase; Digestive diseases; Intestinal disease; Colon; Lymphoblastoid cell
• ISSN: 0955-3002; 1362-3095
• DOI: 10.1080/09553000110050056

Purpose : To investigate whether cells from hereditary nonpolyposis colorectal cancer (HNPCC) patients, a genetic condition characterized by constitutional mutations in DNA mismatch repair genes and associated with predisposition to colorectal carcinoma (CRC), could present a higher G2 chromosomal radiosensitivity. It is generally hypothesized that cancer predisposition in HNPCC is associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair but, to date, no data on G2 radiosensitivity have been reported for HNPCC. Materials and methods : Lymphoblastoid cell lines derived from six HNPCC patients heterozygous for MLH1, one HNPCC patient carrying a mutant MSH2 allele and three healthy controls were treated with 50 cGy of X-rays and sampled at various harvesting times, monitoring cell-cycle progression by 5-bromo-2-deoxyuridine (BrdUrd) incorporation in order to analyse chromosomal damage in the homogeneous G2 population. Results : There were no differences between lymphoblasts derived from patients in the frequency of G2 chromosomal aberrations induced by X-rays when compared with control cell lines. However, despite the absence of G2 radiosensitivity in HNPCC cells, lymphoblasts from patients heterozygous for MLH1 mutations showed a higher induction of chromatid exchanges. Conclusions : The observed possible incorrect rejoining of double-strand breaks in MLH1 heterozygotes would be an additional and important factor contributing to loss of heterozygosity in HNPCC patients.