M. De Braekeleer

Fragile sites and structural rearrangements in cancer

SummaryWe retracted information from a computerized databank which contains the cytogenetic findings of 17,000 patients with leukemia and lymphoma. Cytogenetic data from patients with solid tumors were compiled from Dr. Mitelmans catalogue on “Chromosome aberrations in cancer”. We compared the observed distribution of breaks in chromosome bands involved in structural rearrangements with the random distribution of breaks generated by Monte Carlo simulation and showed that a majority but not all of the bands known to contain a fragile site are involved in structural aberrations in cancer and that some of them are associated with specific chromosome structural changes in specific types of cancer.

High-resolution chromosomal localization of the β-gene of the human β-globin gene complex by in situ hybridization

A 4.4-kb PstI fragment containing the entire beta-gene of the human beta-globin gene cluster plus both 5- and 3-flanking sequences was used as a probe to study the chromosomal localization of the beta-gene by in situ hybridization. Using random oligonucleotides as primers, the beta-gene DNA was 3H-labeled with the large fragment of DNA polymerase I (Klenow fragment) to a specific activity of 1.2 X 10(8) cpm/micrograms. Almost 80% of hybridization grains observed were located on the distal short arm of chromosome 11. High-resolution chromosome analysis suggests a more precise location of the beta-gene to region 11p15.4----p15.5.

Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation

Abstract Cystic fibrosis (CF) has a high incidence in the French-Canadian population of Saguenay Lac-Saint-Jean (Quebec). The A455E mutation accounts for 8.3% of the CF chromosomes. This mutation was shown to be associated with a milder lung disease in the Dutch population. Twenty two CF patients distributed in 17 families and compound heterozygotes for the A455E mutation have been followed at the Clinique de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the ΔF508 mutation while the remaining eight patients had the 621+ 1G→T mutation. Each patient was matched by sex and age to a patient homozygous for the ΔF508 mutation. The pairs were analyzed for several clinical and laboratory variables. The A455E compound heterozygotes were diagnosed at a later age (P = 0.003) and had chloride concentrations at the sweat test lower than those homozygous for the ΔF508 mutation (P = 0.007). More patients were pancreatic sufficient (P = 0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary function tests (P < 0.02). CF patients compound heterozygous for the A455E mutation have a milder pancreatic and lung disease than the ΔF508 homozygotes. Therefore, the A455E should be associated with a better prognosis.

4;11 translocation-associated acute leukemia: A comprehensive analysis☆

A girl with common acute lymphoblastic leukemia associated with t(4;11)(q21;q23) is presented. The physical examination revealed hepatosplenomegaly, and the hematologic analysis showed a high count of white cells. Chemotherapy induced a complete remission (CR), and the patient is still in CR (8 months). At the present time, 43 cases (including ours) of acute leukemia with t(4;11) have been published. This disease more often affects children and women than adult men and is characterized by a high blood white cell count and a short survival. The t(4;11)-associated acute leukemia is a heterogeneous group, including acute undifferentiated leukemia, acute undifferentiated lymphoblastic leukemia, and common acute lymphoblastic leukemia.

The occurrence of the 15;17 translocation in acute promyelocytic leukemia

For many years, acute promyelocytic leukemia (APL) has been associated with the 15;17 translocation. However, questions concerning an eventual geographic distribution have been raised by the Second and Fourth International Workshops on Chromosomes in Leukemia. Using a statistical approach, we showed that, even if the techniques of processing play an important role in detecting the 15;17 translocation, a geographic distribution exists, which is difficult to explain. Finally, we discuss the possible role of c-erb A1 in acute promyelocytic leukemia.

Breakpoint distribution in variant Philadelphia translocations in chronic myeloid leukemia

A statistical analysis of the 327 cases of variant Philadelphia chromosome so far reported in chronic myeloid leukemia was performed. The results showed 28 bands to be significantly rearranged; 11 bands are known to contain a fragile site; 12 are included in the smallest region of overlap of 14 proto-oncogenes. Also, 23 bands are known to be significantly involved in structural rearrangements in other malignancies.

A case of acute lymphoblastic leukemia with t(10;19)(q26;q13)

We report a patient with non-B non-T acute lymphoblastic leukemia (ALL) who has translocation t(10;19)(q26;q13), which has not been reported previously. A brief review of the translocations involving chromosome #19 in ALL is also presented.

Three steps mutation model of carcinogenesis

Abstract Based on recent data, this model supposes that benign and malignant tumors arise when a specific mutation takes place in a specific protein-kinase encoded by a proto-oncogene in a pluripotent stem cell or a committed stem cell. Protein-kinases which are regulated by tissue growth stimulating factors, tissue growth inhibiting factors and differentiating factors phosphorylate specific proteins that can derepress specific genes leading to cell division and cell differentiation. Malignant tumors arise when three mutations happen in a same pluripotent stem cell or committed stem cell: • - positive mutation at the level of tissue growth stimulating factor; • - negative mutation at the level of tissue growth inhibiting factor; • - negative mutation at the level of tissue differentiating factor. Higher expression of oncogenes and amplification reflect the relationship between tumor and host. Chromosomal rearrangements are secondary events that can be important because they may involve genes which are normally not involved in cell division and cell differentiation.