Chromosome sensitivity to bleomycin-induced mutagenesis in lymphocytes from colorectal cancer patients under 40 years of age.

PURPOSE: The incidence of colorectal cancer in young adults (under 40 years of age) is rare. The reason for the occurrence in these patients may lie in their genetic background. METHODS: We studied chromosomal fragility in peripheral blood lymphocytes of patients under the age of 40 with large bowel cancer. Lymphocytes from 24 subjects were examined: 10 untreated large bowel cancer patients under the age of 40 and 14 age-matched and sex-matched controls. RESULTS: The mean number of spontaneous chromosomal breaks per cells (b/c) was significantly higher in the right-sided large bowel cancer patients (0.23 +/- 0.12 b/c) compared with the control group (0.09 +/- 0.04 b/c; P < 0.01), but with no significant difference between the left-sided colorectal cancer patients and the control group. Lymphocytes exposed to the radiomimetic agent, bleomycin, were arrested in methaphase and analyzed for chromosome fragility. Mean chromosome breaks per cell in the left-sided colorectal cancer patients (1.60 +/- 0.49 b/c) were significantly higher than in either the controls (0.72 +/- 0.31 b/c; P < 0.001) or the right-sided, large bowel cancer patients (0.91 +/- 0.24 b/c; P < 0.05). CONCLUSIONS: The increased spontaneous chromosomal breaks in the right colon, as opposed to the increased mutagen-induced chromosomal breaks in the left colon, might indicate that in young colon cancer patients the occurrence of right-sided colon cancer is more likely to be genetically determined, whereas in left-sided colon cancer, environmental carcinogens might play a greater role.

Chromosome 20 long arm deletion in an elderly malformed man.

A 46,XY/46,XY,del(20)(q13-->q13.33) mosaicism was identified in a 68 year old man who had mild mental retardation and severe malformation of the limbs. The clinical findings of the patient are compared to those of the very few cases of 20q deletion published to date.

Cytogenetic studies in patients with gastric cancer.

Banded cytogenetic studies of gastric carcinoma are still relatively scarce, comprised of only a small number of patients. This study was performed on peripheral blood lymphocytes and malignant cells of 16 patients with gastric carcinoma. The lymphocytes were analyzed by standard techniques. All patients had a normal constitutional karyotype; 90% of the patients presented an increased breakage rate and nonrandom chromosomal instability mainly in the heterochromatic regions of chromosomes 1, 9, and 16. Decreased response to phytohemagglutinin was observed in 6 (38%) patients. The tissue specimens were analyzed using direct techniques. Normal ploidy was observed in only one patient, 3 tumors were near-diploid, 4 hyperdiploid, 4 near-triploid, and 4 near-tetraploid. Those with the near-triploid or near-tetraploid constitution were in a more advanced pathological stage, most of them with a more complex cytogenetic profile. Particular involvement was found for chromosomes 1 to 4, 7 to 9, 17, and 20, but the more specific nonrandom changes seemed to involve chromosomes 7, 8, 9, and 17.

Chromosomal anomaly and malformation syndrome with abdominal polyorchidism.

We describe a neonate who presented with multiple severe malformations including polyorchidism. To our knowledge this is the second case reported with ipsilateral testes located intra-abdominally. Chromosomal studies in cases of polyorchidism have been reported previously only once and the patient exhibited a normal karyotype. Our patient had a chromosome 21 long arm deletion. Interestingly, a trisomy 21 patient has been reported with agonadism. We suggest that genes on chromosome 21 may have some role in gonadal development.

Chronic Myelogenous Leukemia Associated with Extranodal B-Cell Lymphoma.

A 75-year-old man is reported with a 10 year-history of villous adenoma of the colon and carcinoma in situ treated by hemicolectomy. Seven years later, he developed chronic myelogenous leukemia (CML). After a 3-month course of busulfan he was kept off chemotherapy for a one year period. Two years after the diagnosis of CML, an extranodal B-cell lymphoma developed in the left ankle region. A clonal pericentric inversion of chromosome 20 was shown in the lymphoma cells, but without Philadelphia (Ph') chromosome. The possible relation between the two malignant disorders is discussed in the light of current knowledge on the clonal origin of CML.

Ca antagonist verapamil and tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA) induce chromosomal aberrations in human lymphocytes.

Lymphocytes from 8 healthy donors were cultured for 3 days in the presence of phytohemagglutinin. Addition of the Ca antagonist verapamil or the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increased chromosomal aberrations in comparison with control cultures. The effects of TPA and verapamil were additive. Although the Ca ionophore A23187 had no effect per se, it did abolish the effect of verapamil. Five patients with supraventricular tachycardia were treated clinically with verapamil for 1 week. Their lymphocytes were cultured for 3 days in vitro in the presence of phytohemagglutinin. These lymphocytes showed higher chromosomal aberrations in comparison with lymphocytes isolated from the patients before treatment. The clinical significance is still unclear. We suggest that calcium ions may be necessary for the intactness of chromosomes of human lymphocytes and presumably of other cells.

Free proximal trisomy 21 in the mother and malformation syndrome in the son.

We report on a new case of duplication of the proximal part of the long arm of chromosome 21. The proposita presents normal mental development, no trisomy 21 manifestations; on the contrary, she had a few monosomy 21-like stigmata. She gave birth to a severely malformed infant with a pattern of malformations suggesting a partial 21-monosomy syndrome, but with a 46,XY normal karyotype in his peripheral blood lymphocytes. The findings are explained in the following way: the infant probably had originally a 47,XY,+21q- karyotype like his mother. Post zygotic nondisjunctional events produced a prevalent 46,XY,21q- line responsible for the severe malformations and the normal 46,XY line found in his blood lymphocytes.

Interstitial deletion 2q14q21.

A girl with multiple congenital anomalies and a tendency to severe pyogenic infections was found to have an interstitial deletion of chromosome band 2q14----q21. Unusual facial manifestations included enophthalmos, long philtrum, micrognathia, narrow forehead, prominent glabella, and depressed nasal bridge. Unilateral corneal clouding, with Peters-like anomaly; agenesis of the corpus callosum; brain atrophy; and heart, kidney, hand, and dermatoglyphic anomalies were additional findings. Eye anomalies were observed in five of 22 patients with deletions of chromosome 2q. In comparing these cases, it seems that deletions of bands 2q21 and 2q31 are variably associated with microphthalmia, corneal clouding, cataracts, and Peters anomaly. Measurement of protein C and interleukin-1 (IL-1) did not show a gene dose effect, but the pyogenic infections and low IgA found in this patient may reflect an abnormality of IL-1 not detectable by our methods.

Fibrous dysplasia and cherubism as an hereditary familial disease. Follow-up of four generations.

Five cases of dysplasia of the jaws in one family which has been under our observation since 1970 are reported. The disease appeared as a mixed display of jaw lesions, in some members as fibrous dysplasia and in others as cherubism. We were able to trace the disorder through an unbroken line of four generations, and thus to demonstrate autosomal dominant inheritance. Cytogenetic analysis performed on three members of this family revealed a significantly increased rate of chromosomal breakage.

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.

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

Bloom's 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 Bloom's 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.

Fragile X expression in Martin-Bell syndrome, intellectually normal individuals, and neoplasia, interpreted by a viral hypothesis.

We present data on fragile X expression in lymphocytes obtained from the following patients: a university student, an infertile couple, 6 of 22 prostatic cancer patients, a meningioma patient, and members of families with meningioma and familial gliomas. All patients were of normal intelligence. In addition, we report 3 cases of central nervous system (CNS) tumors in more typical fragile X families. We suggest that the fragile X expression as well as the clinical findings may be caused by a viral (or similar) infection. The virus may require a receptor protein coded by one allele of a gene on the X chromosome.

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.

Chromium chloride induces chromosomal aberrations in human lymphocytes via indirect action.

The aim of this study was to examine the possible clastogenic effects of trivalent chromium chloride (CrCl3) as the results in the literature are non-conclusive. Under the conditions used in this study Cr(III) induces chromosomal aberrations in phytohemagglutinin(PHA)-stimulated human lymphocytes. This activity, however, is suppressed by the antioxidants superoxide dismutase (SOD) (scavenger of O-.2), the SOD-like agents, catalase and mannitol (specific scavenger of OH.). The possibility that oxygen free radicals could evolve through stimulation of the arachidonic acid cascade is suggested using suitable inhibitors.

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.

Alpha-interferon and fragility at 16q22. A study on 15 selected controls and 146 selected patients.

Inducibility or enhancement of fragility at 16q22 by alpha-interferon has been found in a Danish laboratory and in our laboratory. Several other studies were not able to confirm these findings. We present the results of a large study on peripheral blood lymphocytes of 15 selected controls and 146 selected patients treated in vitro by alpha-interferon. In some of our patients parallel studies with distamycin A were performed. Both interferon and distamycin A induced the same fragility, but only in some patients. Both agents were not consistently able to enhance a spontaneously expressed 16q22 fragility. 16q22 is the location of the metallothionein genes, whose transcription is induced by interferon. The induction of the metallothionein gene transcription and the 16q22 fragility, however, do not seem to be directly related. To explain our findings we advance the hypothesis that fragility at 16q22 may be a modification induced by virus(es) with selective tropism for cells which are differently influenced by a pleiotropic action of interferon.

Interstitial 7q deletion [46,XY,del (7) (pter----cen::q112----qter)] in a retarded quadriplegic boy with normal beta glucuronidase.

A 14-year-old severely retarded male with deletion of chromosomal band 7 cen----q112 is described. Clinical features include short stature, microcephaly, unusual facies with narrow forehead, short nose, malar hypoplasia, protruding alveolar ridges and incisors, receding chin, relatively long philtrum, and large ears. In addition, he had bilateral inguinal herniae cryptorchidism with hypogonadism, pulmonic stenosis, and spastic quadriplegia. Normal activity of beta-glucuronidase was found in the patient's leukocytes. This finding suggests that the gene is not in the deleted region, narrowing the smallest region of overlap to 7q112----q22.

Different inducibility and possible significance of several concomitant "fragile sites" in two brothers.

Concomitance 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.

Familial fragile site found at the cancer breakpoint (1)(q32). Inducibility by distamycin A, concomitance with fragile (16)(q22).

A 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.

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.