Structural Chromosomal Aberrations

A. Translocations, Chromosomal Breaks, and Fragile Sites

Chromosomal translocations are structural aberrations characterized by relocations of chromosomal segments within one or among different chromosomes. As chromosomal translocations are relatively stable structural changes (76-78), they would be expected to accumulate with age. Several investigators have found that the increase in translocation frequencies in a nonsmoking normal population follows a curvilinear relationship with age (79,80). Although ionizing radiation is known to induce chromosomal translocations, it cannot alone account for the strong age-related increase of chromosomal translocations (80). It has been argued that age may play a role in an individual's response to radiation exposure, as the capacity of DNA repair mechanisms may decline with age (81,82). However, it has been demonstrated that the susceptibility to translocation formation induced by acute (83) and chronic (80) ionizing radiation does not change with age. Apparently, other factors are involved in this process.

Marlhens and coworkers (84) have analyzed the incidence of structural chromosomal alterations in young (<30 years) and old (>70 years) probands. Their study shows that chromatid and chromosomal breaks are most likely to in crease as a function of age, with an estimated factor of three to four from 30-75 years. There are several "hot spots" for chromosomal breakage at well-known fragile sites, such as 3p14.3 and Xq27 [fra(X)]. These sites were affected in up to 3% of cells from older individuals. The observation of isolated cells exposing fragile sites therefore must not be considered to be a pathological finding but a normal age-related characteristic.

Terminal deletions occur at a lower incidence, with a maximum of 2 per 100 cells. Their age-related increase is not significant. Most frequently, chromosome 9 and the X chromosome are affected, but these sites—particularly prone to deletions—do not correspond to the most common fragile sites. As for the analysis of chromosomal translocations (80), the results obtained for chromosomal breakage are fairly homogeneous within different age groups (84). Interindividual variation is also negligible for probands from different ethnic backgrounds (80).

Prieur and colleagues (75) have found that specific translocations involving chromosomes 7 and 14 represent an exception to the frequently observed age-related increase of structural aberrations (Table 2). The frequency of rearrangements among specific bands of chromosomes 7 and 14 is higher in newborns (0.43%) than in adults (0.24%). This excess in newborns is most probably related to rearrangements within the immunoglobulin gene family (85). These rearrangements are mainly generated before birth and in early childhood during differentiation of the immune system. Once this differentiation is complete, rearrangements of immunoglobulin gene family members occur at a decreasing frequency. The average incidence of these specific translocations is low (0.3%) compared with the mean frequency of rearrangements involving other bands (2.5%). Rearrangements of other chromosomal bands follow the "normal" age-related pattern and are more common in adults (3.8%) than in newborns (1.3%). However, this example illustrates the importance of discriminating among different types of structural rearrangements, especially when comparing specific structural aberrations occurring at low incidences.

Table 2 Frequencies of Structural Rearrangements Involving Either Specific Bands or Other Bands in Newborns and Adults
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