Fragile sites and bladder cancer

Continued reports of associations between environmentally induced chromosomal fragile sites and cancer prompted us to undertake a review of current literature to examine whether there might be a relationship between fragile sites and chromosomal alterations reported for bladder cancer. It was found that more than half (56%; odds ratio [OR] = 4.70) of chromosomal rearrangements reported for bladder cancer were located at 77 (65%) of the 118 recognized fragile sites (OR = 6.88). Furthermore, 55% of the fragile sites implicated coincided with one or more genes that have been associated with human cancer (such as oncogenes, tumor suppressor, relonc, transloc, disorder, apoptotic, and angiogenic genes). The most common fragile sites involved were FRA1D, FRA1F, FRA8C, FRA9D, FRA9E, and FRA11C. This correlation suggests that there may be profiles of genetic damage via fragile site expression that lead to the development of at least a proportion of bladder cancers.     

Fragile sites and cancer breakpoints

To determine whether there might be a statistically significant association between fragile sites and cancer breakpoints, we examined the locations of the 21 fragile sites and the 50 cancer breakpoints recently accepted by the Seventh Human Gene Mapping Workshop. Nine of the 21 fragile sites appeared to be located at or near a cancer breakpoint. The chi-square test for association gives a value of 15.8 (p < 0.001) indicating that there is a very highly significant statistical association between human fragile sites and cancer breakpoints. This association is not narrowly limited to one class of fragile site, such as those sensitive to folate or to one type of cancer, but appears to extend to leukemia, lymphoma, and solid cancer. To more fully understand the meaning of this intriguing association between fragile sites and cancer breakpoints, future research will need to locate additional fragile sites and cancer breakpoints with precision, record their concurrence in individuals and families, determine if fragile site families are predisposed to cancer, and prove that a fragile site and a cancer breakpoint that appear to be coincident are at the same point on the DNA level.     

Fragile sites, Alzheimer's disease, and aging.

The fragile site expression under conditions of folate deprivation was compared in the chromosomes from 5 Alzheimer's disease (AD) female patients, 5 healthy elderly females and 5 healthy young females. Although different fragile sites were observed in the three groups, nevertheless, more similarities were found between the AD patients and elderly normal donors. The only fragile site common to all groups was 3p14. This site was the most frequent in the young donors group. In both AD and elderly control groups we observed a higher frequency of fragility in 6p21, but not in the young controls. Other interesting fragility points observed in these two groups were: 6q21 and 14q24 (in the AD patients) and 9q13, 14q24 and 17q21 (in the healthy aged). 6p21 and 17q21 have been proposed as 'new' fragile sites. We confirm the existence of these fragile sites and comment that in these bands the genes MTBT2 and MTBT1, which are microtubule (beta) associated protein tau-like and tau 1, respectively, are mapped. The tau protein is a component of paired helical filaments which accumulate in degenerating neurons in the brain of patients with AD and with less intensity of normal elderly individuals.     

Fragile sites are unrelated to reciprocal translocation breakpoints

In 492 cases of reciprocal translocations in balanced carriers, the 984 breakpoints were studied for a possible relationship to the 45 fragile sites. Random coincidence was predicted at 14% and the observed coincidence was 14.3%, indicating that the two events are unrelated. However, chromosomes 1, 11 and 14 were exceptions and did show a statistically significant relationship.     

Fragile sites limited to lymphocytes: molecular recombination and malignancy

Fragile sites on chromosomes are points at which rearrangements tend to occur nonrandomly. Because translocations between chromosomes #7 and #14 occur nonrandomly in normal cultured lymphocytes, we analyzed chromosomes #7 and #14 in 53,580 cultured lymphocytes and 109,300 other human cells. We found one rearrangement per 1,218 lymphocytes. These rearrangements were not restricted to translocations but included inversions and hitherto undetected duplications and deletions. In lymphocytes cultured for only 48 hours, rearrangements were seen indicating their presence in vivo. The breakpoints were exclusively in chromosome bands 7p13, 7q35, 14q11, and 14q32. The predisposition to form these rearrangements appeared nonrandom and inherited. These four bands act as if they contain fragile sites limited to lymphocytes. Fragility was not observed in these bands in cells from amniotic fluid, bone marrow, skin, or chorionic villi. Bands 7p13, 7q35, and 14q11 contain T-cell receptor (TCR) genes, whereas, band 14q32 contains the immunoglobulin heavy (IgH) chain locus. Rearrangements of these bands may result from molecular recombination between TCR or between TCR and IgH genes forming TCR/TCR and TCR/IgH chimeric genes important to understanding lymphocyte development and neoplasia. TCR/IgH chimeric genes have been found in T- and B-cell malignancy.     

Neuroendocrine tumors of genitourinary tract: Recent advances

Primary neuroendocrine tumors of the genitourinary tract are rare and are comprised of a heterogeneous group of neoplasms. These include paraganglioma, well-differentiated neuroendocrine tumors or carcinoid tumors, small-cell neuroendocrine carcinoma, and large-cell neuroendocrine carcinoma. Personal experiences, in addition to the findings of an extensive literature search for pertinent publications, were used to compile the epidemiological data, clinical information, histopathological features, prognostic factors, and therapeutic approaches. We also include molecular alterations and targeted treatments of the various neuroendocrine tumors of the genitourinary tract.     

Fragile sites and chromosome breakpoints in constitutional rearrangements I. Amniocentesis

Since fragile sites may conceivably predispose to chromosome breakage and rearrangements in meiosis, we examined the locations of 278 breakpoints leading to chromosome rearrangements detected in amniocenteses. Of the 278 breakpoints, 59 (21%) were observed to be in bands containing fragile sites compared to an expectation of 31 (11%), a highly significant difference (P less than 0.001). The tendency for breakpoints to be in bands with fragile sites was independent of origin of the rearrangement or class of fragile site, consistent with the concept that fragile sites predispose to heritable chromosome rearrangements.     

Fragile sites and high-resolution chromosome studies in multiple endocrine neoplasia type 2A

Affected individuals from four kindreds with multiple endocrine neoplasia type 2A syndrome (MEN-2A), were studied for the possible existence of a specific fragile site that might be associated with the MEN-2A gene. The chromosomes were also examined with high-resolution banding with particular emphasis on those chromosomes (#1, 10, 20, and 22) that have been implicated by previous studies from several laboratories as being associated with this disease. There was no evidence for a unique fragile site or a unique high-resolution banding pattern in subjects with MEN-2A. These findings, in combination with all previous cytogenetic studies, indicate that it is unlikely that current techniques will be useful in developing a simple cytogenetic test for this disease.     

Cluster of trisomy 12 to tumors of the female genitourinary tract

A patient with a megakaryocytosis associated with a Philadelphia chromosome-positive chronic myeloid leukemia (CML) was found to have a trisomy of chromosome five. To our knowledge, this is the first case of trisomy 5 associated with a Ph + CML, particularly one with a megakaryocytosis. The trisomy 5 may be associated with the resistance to cytostatic drugs found in this patient.     

Fragile sites at 4q23 and 7q11.23 unique to bone marrow cells

Fragile sites in chromosome bands 4q23 and 7q11.23 were discovered in bone marrow cells. Expression of these fragile sites was induced by treatment of the cells sequentially with 10(-7) M methotrexate and then 10(-5) M thymidine. No expression was observed in bone marrow cells without treatment. The fragile sites at 4q23 and 7q11.23 were seen individually, together, and in the homozygous state in a total of 20 bone marrow samples. The bone marrow karyotypes were normal in all cases. Expression of these common fragile sites at 4q23 and 7q11.23 could not be induced in blood lymphocytes from two subjects using methotrexate and thymidine, or by any other means including the addition of bromodeoxyuridine and fluoro-deoxyuridine or growth in folate-deficient medium. Because the fragile sites at 4q23 and 7q11.23 have never been observed in lymphocytes treated with methotrexate and thymidine for high-resolution chromosome analysis, it appears that these fragile sites are not expressed under these conditions in T lymphocytes. We propose that the differential expression of these fragile sites in bone marrow cells reflects genes active in bone marrow cells but not in blood lymphocytes.     

Fragile sites, cancer chromosome breakpoints, and oncogenes all cluster in light G bands

Fragile sites tend to be bands where breaks occur in cancer chromosome rearrangements that can involve oncogenes. The locations of fragile sites, cancer breakpoints, and oncogenes were therefore charted. All were predominantly in light G bands. Specifically, 78 of 89 (88%) fragile sites were in light G bands including the large group of common fragile sites inducible with aphidicolin (p less than 0.001). Of 61 cancer breakpoints, 50 (82%) were in light bands including translocation breakpoints (p less than 0.001). Thirteen of 14 (93%) oncogenes localized to light bands. The sharing of chromosome bands can stem from a biologically meaningful relationship, as between cancer breakpoints and oncogenes. Joint occupancy of chromosome bands can also reflect independent reasons to be in the same sector of the genome. Thus, fragile sites may well be in light bands because they are associated with active genes. This clearly does not rule out a biologic relationship between specific fragile sites and specific cancer breakpoints.