The data at hand derived from some recent investigations of the chromosomes of human tumors have shown that the most frequently occurring tumor cells which have a characteristic number mode (or modes) along with a particular chromosome ideogram (or ideograms) form a stem-line (or-lines) of tumor cells which are the primary progenitors of growing neoplasms, in parallel with the evidence presented by the chromosome analysis of rat and mouse ascites tumors (Hasen-Melander, Kullander & Melander 1956, Levan 1956, Ising & Levan 1957, Manna 1957, Wakabayashi & Ishihara 1958, Makino, Ishihara & Tonomura, 1959). Since the chromosome conditions of human tumors are important in the consideration of the general clinical and pathological properties of neoplasms, the karyological data of human tumors have strikingly aroused a great deal of interest in the medical field. The present paper reports the results in some detail of a chromosome analysis in tumor cells of a human gastric carcinoma in ascites form, with special regard to certain chromosomal features in relation to the therapeutic data.

Exposure of bone marrow cells to alpha-particle radiation causes various types of chromosome abnormalities and hematological malignancies. We performed chromosome analysis of hematopoietic stem cells from the bone marrow of 52 Japanese patients with thorotrastosis and 21 age-matched controls. The frequency of cells with stable chromosome abnormalities was significantly higher in the patients with thorotrastosis. Further studies found 14 clonal chromosome aberrations in cells from 11 patients (21.2%); clones observed in the cells from 2 of these patients had high frequencies of chromosome abnormalities. In one case, 68 to 100% of the cells analyzed had a large partial loss in the short arm of chromosome 1 and a translocation between the short arms of chromosomes 2 and 3 [46,XY,1p-,t(2p+;3p-)]. The cells from the other patient contained a clone with partial loss of both the short and long arms of chromosome 5 (46,XX,5p-,5q-). The frequency of this clone has been constant for the last 15 years (6-24%). We also analyzed bone marrow mononuclear cells from 17 of the patients for mutations of the TP53 tumor suppressor gene (formerly known as p53). However, no mutation was found in any of the cells, including those from the 2 patients with abnormal clones. Moreover, repeated medical examinations showed no evidence of leukemia or myelodysplasia in these patients. Our study suggests that exposure of bone marrow cells to alpha-particle radiation may induce clonal chromosomal aberrations at a high frequency.

I regard it as a great honor and a pleasure to accept the invitation to contribute an article for this special volume of Cancer Genetics and Cflogenetics in celebration of Dr. Avery A. Sandberg's 75th birthday.I spent three fruitful years with Dr

The Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myelogenous leukemia (CML). Whereas the majority of Ph-positive CML patients show the standard Ph translocation involving chromosomes 9 and 22, t(9;22)(q34;q11), the minority of cases exhibit a variant type of Ph translocation involving these two and other chromosomes (complex type) or those involving #22 and chromosomes other than #9 (simple type). To get an insight into the nature of variant Ph translocations and the process of their formation, we examined the localization of the c-abl and c-sis oncogenes and the breakpoint cluster region (bcr) gene by chromosomal in situ hybridization in ten variant Ph translocations of CML including five simple and five complex ones as initially interpreted. In situ hybridization showed that c-abl localized to band 9q34 and c-sis localized to band 22q12-q13 were translocated on the Ph and on one of the rearranged chromosomes other than #9, respectively, in all the variant translocations examined. On the other hand, bcr localized to band 22q11 was translocated on various chromosomes but mostly on chromosome 9. Parallel Southern blot analyses on DNA from leukemic cells of five patients including two with simple translocations and three with complex ones revealed rearrangements of bcr with breakpoints occurring mostly in a 5' portion of 5.8-kb BamHI/BglII sequences, which are quite similar to those detected so far in CML cases with the standard Ph translocation. The present findings strongly suggest that variant Ph translocations of CML are all complex, and some of them are formed stepwisely from the standard translocation.

Fragile site studies were performed on a total of 126 patients with leukemia and other hematologic disorders including myelodysplastic syndrome (MDS) and polycythemia vera (PV). Compared with an incidence (6.0%) of heritable rare fragile sites in the healthy population, the frequency was not higher in the patient group (3.2%), as a whole. However, two cases of fra(17)(p12) in MDS appeared fourfold larger than expected for this group of patients. In one case, a homozygous carrier of fra(17)(p12) in PV was also very rarely expected from its population incidence. These findings suggested a possible role of rare fragile sites, at least in the etiology of these preleukemic or myeloproliferative disorders.

The nature of the Philadelphia (Ph) translocation and the process of its formation were studied by attempting various chromosome banding analyses of variant Ph translocations among 210 patients with Ph-positive chronic myelocytic leukemia examined at the National Institute of Radiological Sciences, Chiba. The following assumptions could be drawn from the results of the analyses: 1) The involvement of specific regions of chromosomes #9 and #22, q34 and q11, respectively, is an indispensable condition of the Ph translocation. 2) The so-called variant Ph translocations are all complex and are derived from a standard Ph translocation. 3) The Ph translocations, both standard and complex ones, are not always stable. The complex translocations are subject to further chromosome evolution, as is the conversion of the standard translocation to complex translocations. There seems to be no fundamental difference between the standard and complex Ph translocations, with the latter being merely a more progressed form of the former. Analyses at the molecular level of the same cases employed in this study are yielding results that support the above assumptions.

Fragile sites were analyzed in normal peripheral lymphocytes from two acute nonlymphocytic leukemia patients with t(7;11)(p15-p13;p15) leukemic cells. To induce expression of fragile sites, cultures were exposed to folate deprivation (M-F10), BrdU, distamycin A, or Hoechst 33258. Fragility at 11p15.1 was induced by distamycin A and Hoechst 33258 but was not seen in M-F10, BrdU, and control cultures. Fra(11)(p15.1) was found neither in healthy Japanese subjects (0 in 845) nor in patients with leukemia or other hematologic disorders without the t(7;11) (0 in 126). From these results, fra(11)(p15.1) can now be calssified as a rare distamycin A-inducible fragile site. Furthermore, this fra(11)(p15.1) coincided with one of the breakpoints of the t(7;11)(p15-p13;p15).

Chromosome analysis was performed in 25 patients with acute nonlymphocytic leukemia (ANLL), mostly of the M2 type. Eighteen had the standard translocation, t(8;21)(q22;q22), four had complex translocations involving 1p36, 11p13, 17p11, and 17p23, respectively, with chromosomes 8 and 21, and the remaining three patients had simple translocations, one with t(3;21)(p14;q22) and two with t(16;21)(p11;q22), without involving chromosome 8. Chromosome abnormalities additional to t(8;21) and its variants that were most frequently observed were −X, −Y, and del(9). Complex translocations are thought to be derived from the standard translocation and to be essentially similar in nature. The finding that chromosome 21 was involved in all of the standard, simple, and complex translocations, and that chromosome 8 was not involved in simple variants suggest a greater weight of chromosome 21 in the relative importance of the two chromosomes to the genesis of ANLL.

To determine the baseline frequency of autosomal rare fragile sites in cancer patients, we conducted a population cytogenetic study of 370 patients with leukemias, solid tumors, and other neoplastic disorders. Twenty carriers of rare fragile sites were detected in this patient group. The rare autosomal fragile sites were at fra(8)(q24), fra(11)(p15), fra(16)(p12.1), fra(16)(q22), and fra(17)(p12). All of these fragile sites were found to be distamycin A inducible. Compared with a population incidence in healthy subjects (44 of 845, 5.21%), the overall incidence of distamycin A-inducible fragile sites was not higher in the patient group (20 of 370, 5.41%). Analysis of these individual fragile sites and particular diseases, however, suggests that the distamycin A-inducible fragile sites may play a role in the etiology of leukemia, myeloproliferative disorders, and benign tumors.

A patient with a constitutional bisatellited supernumerary marker chromosome developed a large cell lung carcinoma and subsequent acute nonlymphocytic leukemia (ANLL) of the M2 type showing an (8;21) translocation and del(9). The ANLL-M2 appeared to be independent of the lung carcinoma. The presence of the supernumerary chromosome might have been associated with the development of the two diseases.