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INDIVIDUAL RADIOSENSITIVITY AND ITS RELATION TO COLO-RECTAL CANCER

Objective

In human populations, heterozygote carriers for the gene of familial adenomatosis polyposis coli (APC), mapped on chromosome 5, are highly predisposed to form polyps and subsequently adenocarcinomas of the colon.

This process of carcinogenesis is not simple. Several other genomic alterations are usually involved, and a susceptibility of these individuals to various mutagens is suspected. A study is underway to look for an eventual chromosomal instability in the patients, in lymphocytes and epithelial cells from polyps and adenocarcinomas. In addition, studies on radiation sensitivity of the lymphocytes are being conducted by comparing, in the same families, affected and nonaffected relatives, using cytogenetic and molecular techniques.
A study has been carried out on patients affected by familial adenomatous polyposis coli (APC). Genetic analysis has been performed on deoxyribonucleic acid (DNA) from peripheral blood of 260 persons from 25 families. The use of 12 probes for polymorphic loci from the APC region of chromosome 5 provided significant information on either side of the gene. This allowed an estimate of risk in developing APC to be determined for young relatives.
Cytogenic studies on nonirradiated lymphocytes from 12 APC and 12 non-APC colorectal cancer patients showed that both groups have similar rates of chromosome breakage and aberrations and that these were not high in comparison to controls.

A study has been carried out of the cytological and cytogenetical radiosensitivity of blood cells from CPA carriers and normal individuals from the same family. Results showed that interindividual variations exceeded the differences between the groups of CPA carriers and normal individuals.

Deoxyribonucleic acid (DNA) breakages after gamma irradiation of peripheral leucocytes have been studied in familial adenomatous polyposis (FAP) patients and controls. FAP patients tended to show greater DNA breakage but this was not statistically significant.
Ascertainment of the cases and characterization
Patients are first ascertained on clinical criteria, in various specialized consultations and clinics of the Paris region. When an APC syndrome is suspected a familial analysis is performed and a pedigree established. Then, blood samples of members of the family are obtained. Aliquots of these samples are used for DNA extraction. DNA is cut by different restriction enzymes permitting the detection of polymorphisms, with tested markers located on both sides of the APC gene. Then, using Southern's technique, the haplotype of the chromosomal segment 5q21-q22 is established for each individual.
The 2 haplotypes of each individual are compared with those of their relatives to determine which one is associated with the disease and to localize the mutant gene. This part of the work is performed by the group of Gilles Thomas at the Institut Curie (Paris).

Cytogenetic analysis
These have developed in several directions:
characterization of spontaneous chromosomal anomalies in blood lymphocytes;
cytogenetic study of benign and malignant tumours;
effect of radiation on blood lymphocytes.

DNA breakage analysis
Blood samples from APC patients are irradiated by X-rays at doses of 0.2 1 and 2 Gy. DNA breaks are analyzed using fluorometric analysis of DNA unwinding (FADN) method. The role of DNA repair systems and in particular the activity of poly (ADP-ribose) polymerase is studied in relation to the production of DNA breaks and the kinetics of DNA repair.

The part played by active oxygen species through modulation of endogenous levels of catalase activity and usage of OH scavengers is also studied. This part of the work, performed on blood samples obtained locally, is developed by the Department of Genetics of UNL (Lisbon). Another study will be done by the same group on lymphoblastoid cell lines from APC patients developed at the Institut Curie (Paris).

Coordinator

Participants (2)

UNIVERSIDADE NOVA DE LISBOA
Portugal
Address
Campus De Campolide
1099 085 Lisboa
UNIVERSITE CATHOLIQUE DE LOUVAIN
Belgium
Address
Place De L'universite 1
Louvain-la-neuve