Relationship between fragile sites and cancer breakpoints

LETTERS TO THE EDITOR Relationship Between Fragile Sites and Cancer Breakpoints Conflicting reports have been published regarding the association of cancer translocation breakpoints in malignant cells occurring at fragile sites found in normal tissue [1]. I propose that this discrepancy can be explained if breakage is a relatively r a n d o m p h e n o m e n o n . Fragile sites are c o d o m i n a n t l y inherited n o n s t a i n i n g gaps or breaks that occur at specific chromosome locations [2]. C o m m o n fragile sites are ubiquitous whereas rare fragile sites are familial. To date, 107 rare and c o m m o n fragile sites have been d o c u m e n t e d [3], comprising 98 bands at the 400 haploid band length. Laird et al. [4] hypothesized that the susceptibility to breakage at fragile sites results from i n h e r e n t late DNA replication which can be induced by cell culturing conditions. Failure to complete DNA synthesis before chromosome c o n d e n s a t i o n results in an unc o n d e n s e d area appearing as a gap or break which is observed in some but not all cells. DNA instability is believed to explain the i n v o l v e m e n t of rare and c o m m o n fragile sites in evolutionary chromosome rearrangements [5], congenital abnormalities [6], and specific chromosome rearrangements in cancer [7]. Of the 146 cancer breakpoints [8], 52 are associated with fragile sites, which is in excess of those occurring at nonfragile sites (X 2 = 6.645, df = 1, p < 0.001). Cancer breakpoints comprise 53.1% of fragile sites (52 of 98) whereas cancer breakpoints are present in only 31.1% (94 of 302) of nonfragile sites. Our previous studies [9, 10] showed that although more general chromosomal breakage occurs in malignant cells, about half of the breaks in normal and malignant cells are associated with fragile sites whether or not they were i n d u c e d with fluorodeoxyuridine. Although fragile sites are more prevalent in malignant cells, the percentage of fragile sites is similar in both malignant and normal cells. Because the likelihood of a break occurring at a fragile or nonfragile site is about 50%, breakage is three times more frequent at a fragile site than at a nonfragile site (1 in 98 versus I in 302). If breakage occurs randomly, the probability of a single break occurring at a cancer breakpoint residing at a fragile site is 1/98 × 53.1%, or 0.0054; for a nonfragile site, the probability is 1/302 x 31.1%, or 0.0010. Therefore, the likelihood of a chromosomal break occurring at a cancer breakpoint is 5.4 times more frequent for a fragile site than for a nonfragile site by chance alone. These statistics do not take into account fragile sites that are not expressed in some i n d i v i d u a l s or, in particular, rare fragile sites that are expressed at a high frequency, which would decrease or increase, respectively, the probability of being involved in a cancer breakpoint. In general, however, increased breakage in malignant or premalignant cells, by chance alone, will consequently increase the likelihood of a cancer translocation breakpoint

being associated at a fragile site. Although the chromosomal nature of fragile sites makes them more prone to breakage than nonfragile sites, r a n d o m i n v o l v e m e n t of breakage at specific bands would explain why expressed fragile sites in normal tissue are sometimes (but not always) associated with a related cancer breakpoint. EDITOR'S NOTE

This letter by Dr. Wenger serves to emphasize the statistics needed to examine the possible relationship between fragile sites and cancer. Although some circumstantial evidence m a y connect fragile sites and cancer breakpoints, there is no direct proof, and there is some evidence against a cause-and-effect connection. Whether the premalignant and malignant states lead to increased cytogenetic expression of fragile sites also warrants further consideration. S.L. WENGER

Department of Pediatrics School of Medicine University of Pittsburgh Division of Medical Genetics Children's Hospital of Pittsburgh Pittsburgh, P e n n s y l v a n i a

REFERENCES

1. Cancer Genet Cytogenet 31 (1989):31(1). 2. Sutherland GR (1979): Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte cultures. Am J Hum Genet 31:125-135. 3. Suther|and GR, Ledbetter DH (1989): Report of the committee on cytogenetic markers. Cytogenet Cell Genet 51:452-458. 4. Laird C, Jaffe E, Karpen G, Lamb M, Nelson R (1987): Fragile sites in human chromosomes as regions of late-replicating DNA. Trends Genet 3:274-281. 5. Miro R, Clemente IC, Fuster C, Egozcue J (1987): Fragile sites, chromosome evolution, and human neoplasm. Hum Genet 75:345-349. 6. Hecht F, Hecht BK (1984): Fragile sites and chromosome breakpoints in constitutional rearrangements II. Spontaneous abortions, stillbirths and newborns. Clin Genet 26:174-177. 7. Hecht F, Sutherland GR (1984): Fragile sites and cancer breakpoints. Cancer Genet Cytogenet 12:179-181. 8. Trent JM, Kaneko Y, Mitelman F (1989): Report of the committee on structural chromosome changes in neoplasia. Cytogenet Cell Genet 51:533-562. 9. Becker R, Surti U, Wenger SL (1990): Sister chromatid exchange and chromosome breakage in complete hydatidiform moles. Am J Hum Genet 47:A3. 10. Brooks-Eikenberry HJ, Wenger SL (1990): Chromosome breakage in leukemic bone marrow cells. In Vitro Cell Dev Biol 25:59A. 213

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Cancer Genet Cytogenet 61:213 (1992) 9165-4608/92/$05.00