Barbara K. Hecht

Cancer in Ataxia-telangiectasia patients☆

A gene locus for ataxia-telangiectasia (A-T) is in chromosome region 11q22 to 11q23 and predisposes to cancer. Ataxia-telangiectasia patients appear to have two separate clinical patterns of malignancy. One pattern involves solid tumors, which have not been stressed and which include malignancies in the oral cavity, breast, stomach, pancreas, ovary, and bladder. Detection of a solid tumor in an A-T patient should serve as a warning. It heralds a markedly elevated risk of another malignancy in that patient. The second pattern of neoplasia in A-T is well recognized and consists of lymphocytic leukemia and non-Hodgkins lymphoma. These malignancies may relate to immunodeficiency in A-T and to chromosome breakage and rearrangement, which are a feature of A-T. These two patterns of malignancy may be truly separate and reflect different mechanisms of malignancy in A-T, or they may not really be separate but instead reflect a single mechanism of malignancy. The situation in A-T is reminiscent of that in the acquired immunodeficiency syndrome (AIDS), in which Kaposis sarcoma occurs with mild immunodeficiency and pneumocystis carinii pneumonia occurs with more profound immunodeficiency owing to the human immunodeficiency virus. Next to pulmonary disease, cancer is the leading cause of death in A-T.

BCL3 rearrangements and t(14;19) in chronic lymphocytic leukemia and other B-cell malignancies: A molecular and cytogenetic study

The t(14;19)(q32.3;q13.1) is a recurring translocation found in the neoplastic cells of some patients with chronic lymphocytic leukemia (CLL) or other B‐lymphocytic neoplasms. We previously cloned the translocation breakpoint junctions present in the leukemic cells from three such patients and identified a gene, BCL3, whose transcription is increased as a result of the translocation. In the present paper, we describe three additional patients with the t(14;19), one with lymphoma and two with CLL, and report the cloning and sequencing of the breakpoint junction in one of these patients as well as in a previously reported patient. We and others have found that the breakpoints on chromosome 14, with one exception, fall within the switch region upstream of the immunoglobulin heavy chain Cα1 or Cα2 sequences. Several of the breaks within chromosome 19 fall immediately upstream of the BCL3 gene, but several others are more than 16 kb 5′ of the gene. Most patients with CLL and the t(14;19) also show trisomy 12. Genes Chromosom. Cancer 20:64–72, 1997.

Regional chromosome localization of human papillomavirus intergration sites near fragile sites, oncogenes, and cancer chromosome breakpoints

The integration sites of human papillomavirus (HPV) DNA within the cervical carcinoma cell line C4-I and a primary cervical tumor were mapped by in situ hybridization. Cloned cellular sequences flanking the integrated viral DNA were used as probes. For the cell line, the viral integration site was mapped to chromosome region 8q21-q22.3, while in the primary tumor chromosome band 3p21 was the target for integration. The HPV DNA integration appears to occur in the vicinity of fragile sites, oncogenes, and chromosome breakpoints that are characteristic of hematologic malignancies and solid tumors. The integration of HPV may thus promote chromosome changes in cancer cells.

New common fragile sites

We report the finding of a large number of new common fragile sites. Thirty-one (56%) of 55 common fragile sites found in a sample of human lymphocytes were ones not described at the Eighth International Workshop on Human Gene Mapping (HGM 8). The sample consisted of 3023 lymphocytes from nine unrelated individuals with a history of genitourinary malignancy. The lymphocytes were challenged in culture with aphidicolin (Apc), fluorodeoxyuridine (FUdR), 5-azacytidine (Aza), and bromodeoxyuridine (BrdU). Thirteen of the new common fragile sites were induced by Apc and FUdR, nine by Aza, five by BrdU, and four by combined means. The sites induced by Apc and FUdR were cross-induced by BrdU. The fragile sites induced by a diminished concentration of Aza were largely located in heterochromatic regions and were cross-induced by BrdU and FUdR. Exposure to BrdU for 24 hours, a technique hitherto restricted to rare fragile sites, induced several common fragile sites. Control lymphocytes had far fewer gaps and breaks, but these were clustered predominantly at high-expression fragile sites. Because more than half of the common fragile sites in this study were new, it is clear that much remains to be learned. Because the classes of fragile sites reveal cross-induction, we propose that fragile sites share structures in DNA.

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<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 chromosome breakpoints in constitutional rearrangements II. Spontaneous abortions, stillbirths and newborns

Certain fragile sites may possibly predispose to chromosome breakage and rearrangements in meiosis. To test this hypothesis, we examined 894 breakpoints found in spontaneous abortions, stillbirths and livebirths of which 165 (18.5%) were in bands with fragile sites. Compared to an expectation of 98 (11%), there was a significant excess of breakpoints in fragile site bands (P<0,001). Together with data from amniocenteses, there is now evidence suggesting that certain fragile sites may be prone to fragility in meiosis.

Histiocytic lymphoma cell lines: Immunologic and cytogenetic studies

Cell lines were established from 15 patients with diffuse histiocytic lymphoma (DHL) of the intermediate grade, diffuse large cell (class G), and high-grade, large cell immunoblastic (class H) types. Immunologic studies indicated that 11 of the 15 DHL cell lines were B cell in origin, 2 were histiocytic, and 2 were null cell. Cytogenetic studies revealed 1 hypodiploid, 11 hyperdiploid, and 3 near-tetraploid cell lines. Chromosome #7 was trisomic in 3 lines, chromosomes #12 in 4 lines, and chromosome #13 in 3 lines. Chromosome #2 was monosomic in 3 lines, chromosome #8 was monosomic in 5 lines, chromosome #14 in 4 lines, and chromosome #22 in 6 cell lines. This is of special interest, as chromosomes #2, #8, #14, and #22 are clearly concerned with rearrangements in Burkitts lymphoma and immunoglobulin expression. The most common rearrangement in the DHL cell lines involved chromosome #14 at band 14q32. However, in contrast to Burkitts lymphoma, the pattern of translocation in DHL is between chromosome #14 and usually chromosome #11 or chromosome #18. The 14;18 translocation is not restricted to patients with low-grade follicular, small cleaved cell lymphomas, as has been reported. The 14q+ chromosome is characteristic of lymphoid malignancies in general. It is due, invariably, to a translocation with the breakpoint in band 14q32, which is the locus of the immunoglobulin heavy chain genes. We propose that in each translocation, for example, chromosomes #11 or #18, an oncogene may be transposed onto chromosome #14, and that each 14q+ translocation in DHL represents an event that transposes an oncogene from another chromosome to chromosome #14.

Translocation (1;7)(p11;p11): A new myeloproliferative hematologic entity

Four cases with myeloproliferative syndromes or acute nonlymphocytic leukemia associated with t(1;7)(p11;p11) are presented. In each case, as in all cases published in the literature, the karyotypes of the affected cells contained two normal chromosomes #1, but only one chromosome #7, with the result that the basic karyotype was 46, -7, +t(1;7). This chromosome change is not geographically restricted, and appears to characterize a group of patients with myeloproliferative disorders and acute nonlymphocytic leukemia, including myeloproliferative syndromes, in whom exposure to previous chemotherapy, x-rays, or drugs is in the background history. The t(1;7) in secondary leukemia and myeloproliferative syndromes serves to duplicate the long arm of a chromosome #1 and to rescue the short arm of a chromosome #7.

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.

The Philadelphia (Ph) chromosome in leukemia. II. Variant Ph translocations in acute lymphoblastic leukemia

Nearly 20 patients with a masked Philadelphia (Ph) translocation have been described in chronic myelocytic leukemia. We report two instances of acute lymphoblastic leukemia (ALL) with variant Ph translocations. One case, involving a 26-year-old male, was associated with a variant t(14;22)(q32;q11) translocation. The second case involved a 36-year-old male with a more complex translocation, t(9;15;22)(q12;q26;q11). In each case, cells with a masked Ph translocation were observed. These appear to be the first ALL cases reported with a masked Ph chromosome. The findings are discussed in relation to recent knowledge regarding the genesis of the Ph chromosome.