Dvora Klar

On the meaning of fragile sites in cancer risk and development.

In the last few years, there has been increasing concern about the possible involvement of fragile sites in cancer risk and development. Patients with malignancies and family histories of cancer who presented with constitutional fragile sites are reported here. These findings are discussed with regard to the familial risk for cancer and the tissue specificity of the malignancy in relation to the different fragile sites. The hypothesis is advanced that these may be sites of viral DNA modification, probably representing areas where genes that are important for the metabolism of the virus are located. On the other hand, these genes may well be cellular (proto)oncogenes. We believe that fragile sites may increase the risk for cancer, not by being break-prone points at oncogene locations, but through more complex mechanisms that are not easy to predict.

Cytogenetic study of patients with carcinoma of the colon and rectum: particular C-band variants as possible markers for cancer proneness

A possible involvement of chromosomal heterochromatic polymorphisms in propensity to cancer has been considered and discussed by several investigators who studied groups of patients presenting with different forms of malignancy. We report a cytogenetic study on the circulating lymphocytes of patients suffering from colorectal carcinoma, most of whom were of European origin. Significantly increased incidence of polymorphisms of chromosomes #1 and #9 was found, especially partial inversions (PI). Emphasis is given to the problem of selecting adequate controls, which must be as homogeneous as possible.

Involvement of chromosome 22 in a Merkel cell carcinoma in a patient with a previous meningioma

The relatively simple cytogenetic findings in an aggressive metastatic Merkel cell carcinoma are reported. Deletion 2p was found in 100% of the cells. Nevertheless, this was considered a secondary (metastatic?) change because the same aberration has been found in several other kinds of malignancy. The involvement of chromosome 22 [del(22q) and -22] in 85% of the cells seemed more intriguing, considering the fact that the Merkel cell carcinoma followed a previous meningioma.

A new familial "fragile site" on chromosome 16 (q23-24). Cytogenetic and clinical considerations

SummaryA new familial fragile site at 16q23-24 is documented, and the clinical and cytogenetic data on three families and some individual patients are reported. The importance of differentiating this fragile site from that recognized previously at 16q22 is pointed out.

Familial fragile site found at the cancer breakpoint (1)(q32)

SummaryA normal baby was cytogenetically examined immediately after birth for the possible presence of a fragile (16)(q22), which had been found in her mother and in her retarded sister with a 46,XX;46,XX,del(16)(q22) mosaic karyotype. Distamycin a was added to the cultures to enhance the fragile (16)(q22) expression. The response of the baby to the action of distamycin a in vitro was much greater than that of her family members. A fragile (16)(q22) was induced in many cells as well as a fragile (1)(q32), which was also found in her mother. This fragile site, which is known to be a cancer breakpoint, has not been reported so far either to be familial or to be inducible by distamycin A. The concomitance of fragile (1)(q32) with fragile (16)(q22) and their possible significance are considered.

Familial fragility on chromosome 16 (fra 16q22) enhanced by both interferon and Distamycin A.

SummaryA family with a “fragile site” at 16q22, inducible by both interferon and Distamycin A, is reported. Immunological problems were found in the family. In a sibship of ten, eight children had died in infancy. Our study led to the conclusions that interferon and Distamycin A induce fragility at the same site, which has the same characteristics as the spontaneous fragile site; that a viral hypothesis for this fragility may be supported; and that immunoincompetence of one kind or another must be considered in families presenting a fragile site at 16q22.

Different inducibility and possible significance of several concomitant “fragile sites” in two brothers

SummaryConcomitance of four fragile sites (at 16p13, 16q22, 16q23, Yq12) in the lymphocyte cultures of two brothers is reported. The expression of each of these fragile sites was enhanced (or induced) by different culture conditions. Some of the inducing conditions are already known and others are reported here for the first time. The meaning of the fragile sites is discussed and a possible viral etiology suggested. Concomitance of some of them may be a potential causal factor for deletions, translocations, or inversions.

Non-random chromosomal aberrations in a complex leukaemic clone of a Bloom's syndrome patient

SummaryBlooms syndrome is one of the congenital disorders known to have increased frequency of acute leukaemia. The complex cytogenetic findings in the leukaemic cells of a 39-year-old male with Blooms syndrome are described. These included a translocation t(7;17), missing 7q and 17p, a reciprocal translocation t(4;22); del 3q, del 8q22, del 20q, missing 12 and missing Y. In the same patient a missing Y had been noted 10 years previously in 15% of his peripheral blood lymphocytes.

Familial fragile 8q22 involved as a cancer breakpoint in cells of a large bowel tumor

A familial fragile 8q22 and an interferon-induced fragile 16q22 were found in two sisters. Eight years previously, both sisters developed an endometrial adenocarcinoma and now one of them presented with an adenocarcinoma of the colon. An 8q22 deletion was found in all the cells of the colonic tumor and seemed to be the primary initiating change. Other nonrandom and possibly promoting aberrations were also present, among others, a 16q22 deletion. The possibility exists that a familial fragile 8q22 may predispose to cancer and a fragile 16q22 may have promoting capacities.

Inversion (16)(p13q22) in tumor cells of sigmoid colon

We report on the cytogenetic findings in direct preparations of two tumors of the sigmoid colon. Respectively, they had a near-triploid and a near-tetraploid constitution and relative numerical and other inconstant chromosomal imbalances. The only constant chromosomal structural anomaly apparently was inversion of chromosome #16, inv(16)(p13q22), which was found in all the cells examined. This rearrangement has been found to be associated with a type of acute myelomonocytic leukemia type M4. We suggest that an etiologic clastogenic (and oncogenic) agent responsible for this rearrangement may eventually be the cause of various kinds of malignancy.