Cytogenetic abnormalities

Detection of specific cytogenetic abnormalities For instance, a small deletion of band Xp21.2 was important in cloning the gene involved in Duchenne muscular dystrophy. 

In both children and adults with ALL, clinical trials have identified several risk factors that correlate with outcome (Table 92-5). Prognostic features include age, WBC count, cytogenetic abnormalities, ploidy, leukemic cell immunophe-notype, and degree of initial response to therapy.7 When these factors are combined, they predict groups of patients with varying degrees of risk for treatment failure. 

TABLE 92-6. Risk Category According to Cytogenetic Abnormalities Present... 

An increased rate of chromosomal abnormalities has been reported for adult-onset schizophrenia (Karayiorgou and Gogos, 1997 Bassett et al., 2000). Cytogenetic abnormalities have been examined in the NIMH COS cohort. Five of our initial 54 patients had cytogenetic abnormalities (a girl with Turner s syndrome, a boy with a balanced translocation of chromosomes 1... 

Cytogenetic abnormalities are frequent in most tumor types and are often associated with tumor characteristics or patient outcome. Altered DNA ploidy (copy number changes) in the cancer genome was described in the 1960s when it was demonstrated that bladder and prostate cancer patients with diploid or tetraploid tumor nuclei had a longer survival rate than patients with triploid or hexaploid tumor nuclei (19). 

An international effort is underway to harmonize methodologies for detecting BCR-ABLl transcripts and kinase domain mutations and adjusting the results so they are standardized from one lab to another (28,29). The availability of a reproducible real-time quantitative PCR (RQ-PCR) has shown in one study that patients with a major molecular response do not have evidence of cytogenetic abnormalities in their bone marrow, and therefore a policy of performing bone marrow biopsies only in patients who have not achieved or have lost a major molecular response would allow many patients to forego the discomfort and expense of multiple bone marrow biopsies (30). 

Chromosomal abnormalities included the presence of aneuploidy, a second Ph chromosome, and trisomy 8. The loss of one p53 allele by an alteration of the short arm of chromosome 17 was seen in seven patients, and new reciprocal translocations were seen in two patients. In eight cases, multiple cytogenetic abnormalities were also present (40). 

In 2005, a study appeared in Cancer Letters that would have evoked widespread media coverage if it had been about an illegal drug, rather than about a pharmaceutical company product (El-Zein, 2005). Researchers from the University of Texas examined 12 children treated with therapeutic effects of Ritalin to determine whether this central nervous system stimulant produces cytogenetic abnormalities in pediatric patients at therapeutic doses. Using peripheral blood lymphocytes taken from the children, they found a 2.4-fold increase in chromosome aberrations and similar defects. They concluded, These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well-documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk. ... 

Shakil, F.A., A. Kuramoto, M. Yamakido, et al. 1993. Cytogenetic abnormalities of hematopoietic tissue in retired workers of the Ohkunojima poison gas factory. Hiroshima J. Med. Sci. 42 159-165. 

In contrast, a nnmber of other studies did not confirm that the G-CSF increases the risk of myelodysplasia or acnte lenkemia, bnt the anthors did not rule out a possible leukemogenic effect. In a stndy of patients with severe aplastic anemia the freqnencies of cytogenetic abnormalities and myelodysplasia or lenkemia were similar in 87 patients treated with G-CSF in addition to immunosuppressive treatment compared with 57 patients who did not receive G-CSF (81). Althongh the authors stated that a leukemogenic effect of G-CSF was unlikely, they mentioned that the median interval of appearance of cytogenetic abnormahties was shorter in the G-CSF group. 

Compared with untreated patients and patients treated with busulfan or hydroxyurea, interferon alfa produced a significantly higher frequency of clonal aberrant cytogenetic abnormalities and chronic clonal evolution in patients with chronic myeloid leukemia (386). However, the possible role of interferon alfa in the secondary occurrence of hematological malignancies is purely speculative. Only isolated cases of myeloproliferative syndrome, leukemia, or lymphoma have been attributed to interferon alfa (SED-13, 1098) (SEDA-20, 331) (SEDA-21, 373). There was no increased incidence of second cancers in patients treated for hairy cell leukemia (SEDA-20, 331). 

Cytogenetic Abnormality Genes or Loci ( ) Involved Disease Clinical Features Frequency of Abberation (%)... 

Paderi S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 1998 91 3995-4019. 

There are several well-known risk factors that correlate with prognosis for ALL. Poor prognostic factors include high WBC counts at presentation, very young or very old age at presentation, delayed remission induction and presence of cytogenetic abnormalities (e.g., Ph+ chromosome). 

Therapy of both ALL and AML are based on specific risk factors such as age or WBC count at time of diagnosis in ALL. For both ALL and AML, cytogenetic abnormalities provide significant information regarding risk stratification and identify subgroups that may benefit from novel molecularly targeted therapies. 

There are several well-known poor prognostic factors for adult AML, and they include older age (>60 years), organ impairment, certain FAB subtypes (FAB MO, MS, M6, M7), presence of extramedullary disease, and presence of cytogenetic abnormalities (i.e., -5, -7, complex karyotype). 

Lymphoid lenkemias are not addressed in the current WHO classification system. Markers on the ceU snrface or membrane of the lymphoblast can be nsed to classify ALL (Table 131-4). ALL may also be described by cytogenetic abnormalities. Chromosome alterations include numerical (hyperdiploidy and hypodiploidy), and structural... 

In both adults and children with ALL, recent studies have identified several risk factors that correlate with prognosis (Table 131-6). As most patients with ALL achieve a CR, these factors correlated with the risk of leukemic relapse rather than the risk of not achieving a CR.. 1 Poor prognostic factors include high WBC count at presentation, very young or old age at presentation, delayed remission induction, and the presence of specific cytogenetic abnormalities. Several specific chromosomal translocations have been iden- tifled and are now being routinely used in risk assessment. 

The National Cancer Institute developed an ALL risk stratihca-tion to create a standard for comparison in children (Table 131-8). Therapy is initially selected based on this classihcation, but may be modified based on the presence or absence of cytogenetic abnormalities, slow response to induction treatment, or CNS involvement. In the adult population with ALL, age <35 years, good performance status, time to CR <4 weeks, timely clearance of blasts, and presenting WBC count of <30,000/mm all qualify as standard risk factors. ... 

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