Acquired Chromosomal Abnormalities

The human genome is inherently unstable with mutations occurring at a low background rate. Most of these changes are lethal and do not survive or they are innocuous and therefore of

DiGeorge syndrome

Type of abnormality: deletion Critical region: 22q11.21-11.23 Thymus hypoplasia or aplasia with deficit in cellular immunity Diminished number of T-cells Hypoparathyroidism Cardiac anomalies Subtle dysmorphic features

Velo-cardio-facial syndrome Type of abnormality: deletion Critical region: 22q11.2 Long face Smooth philtrum Up-slanting eyes Cleft lip and/or palate Long nose with bulbous tip Small mouth

Slender hands and fingers Severe hypernasal speech Learning disorders and psychosis Congenital heart defects no harm to the organism, but others are responsible for diseases like cancer. Most cancers result from an accumulation of several mutations. Although some constitutional factors influence the development of cancer, environmental factors such as exposure to carcinogens and ionizing radiation, diet, and certain viruses and bacteria play a major role. Many mutations involved in tumorigenesis occur at the gene level and cannot be detected cytogenetically, but others involve the presence or absence of chromosomes or chromosomal rearrangements that are visible at the level of the light microscope.

Cytogenetically, cancers can be broadly classified as solid tumors and hematologic disorders. Although solid tumors are most important in terms of human morbidity and mortality, the majority of cytogenetic knowledge about cancers deals with the hematologic disorders. Although our knowledge of solid tumors has increased in recent years, it still lags behind that of hematologic malignancies. This is in large part the result of technical difficulties of obtaining a proper sample, difficulties in culturing cells from solid tumors, and because of diagnostic difficulties of interpreting the chromosomal findings, even if decent preparations can be obtained. Because many solid tumors are discovered at a more advanced stage, the cytogenetic picture can be very complex and difficult to decipher.

Flouresence in situ hybridization has become a very important tool in cancer genetics in recent years, allowing for rapid and easy detection of specific chromosomal abnormalities known to be common in certain cancers. Despite this, conventional FISH approaches only allow for the detection of the specific abnormalities being probed for, so classical cyto-genetics is still important for seeing the larger picture.

Although the cytogenetic changes seen in cancer cells can be very complex and heterogeneous, these acquired changes do not occur randomly throughout the genome. There seems to be a predisposition to breakage at certain sites. Specifically, 83 bands appear to be of primary importance, and breakage at least 1 of these has been reported to be seen in over 95% of tumor with complex cytogenetic changes (29). Cancer genes reside at many of these breakpoints.

There are sometimes particular chromosomal abnormalities that are seen early in tumor development and that might represent an early necessary step in malignant transformation. These are referred to as primary cytogenetic changes and might be seen as the sole abnormality in the tumor cells.

As the tumor develops, additional chromosomal aberrations occur. Many of these are well-documented, nonrandom changes that are never seen as the sole cytogenetic change. They are not necessary for the existence of the tumor, but these secondary changes might give the tumor a growth advantage and represent progression and evolution of the tumor.

Other chromosomal changes appear to be random changes that are unique to a given cell or clone. They might represent unstable mutations that are unable to produce viable cell lines. They are probably not clinically significant and do not appear to play a role in tumor evolution.

Many malignancies show a wide range of chromosomal abnormalities, and many of the most common findings are seen only in a minority of cases. Thus, the abnormalities described must not be considered all inclusive, but they represent some of the more commonly observed changes.

5.1. SOLID TUMORS What follows is just a sampling of the many solid tumors. The reader is referred to other sources for a more complete information on this topic (30-32).

5.1.1. Retinoblastoma Retinoblastoma is a malignant neoplasm of the primitive retinal cells of the eye of young children. Retinoblastoma can be either hereditary or sporadic. The Rb gene is a tumor suppressor gene located on chromosome 13 at band q14. Loss or mutation of both copies of the gene is required for tumor development. Some individuals have a cyto-genetically visible constitutional deletion involving 13q14 that represents the first hit in this two-step process. Other chromosomal changes might also be seen in retinoblastoma. The most commonly occurring cytogenetic change is an isochromosome of the short arm of chromosome 6. This might be seen as a sole change or in conjunction with other cytogenetic changes. Abnormalities of chromosome 1 that result in gains of longarm material are also seen but have not been reported as the sole cytogenetic change.

5.1.2. Wilms' Tumor Wilms' tumor or nephroblastoma is a genetically complex embryonic kidney tumor affecting children under the age of 7 yr. As with retinoblastoma, there are hereditary and sporadic forms. Loci at 11p13 and 11p15 are important and might be involved in primary cytogenetic changes observed in this tumor. Specifically, deletions of 11p13 and duplications of 11p15 can be seen as primary changes. WTI, a tumor suppressor gene, is located at 11p13 and its deletion represents the first hit in tumorigenesis. Several imprinted genes (IGF2, p57, and H19) are located at 11p15 and appear to be involved in development of Wilms' tumor and other cancers. Wilms' tumor might show acquired secondary changes, including whole-arm translocations involving chromosomes 1 and 16 and isochromosomes of the long arm of chromosome 1.

5.1.3. Neuroblastoma Neuroblastoma is one of the small, round, blue cell tumors of childhood. It is a tumor of the neurons of the postganglionic sympathetic nervous system. Deletions involving 1p32-36 are seen as a primary change in as many as 70% of cases. Two possible tumor suppressor genes, NB-R1 and NB-R2, are located in this region and appear to play a role in tumorigenesis. Tumors with deletions of NB-R1 are usually triploid, whereas those with deletions of NB-R2 are diploid or tetraploid. There is a characteristic translocation, t(1; 17)(p36;q12), seen as a secondary change in neuroblas-toma, and gene amplification is seen in about half of the cases. Amplification of the N-myc oncogene located at 2p24.1 results in double minutes (dmin) or, less frequently, homogeneously staining regions (hsr).

Double minutes are small, double structures in the cell nucleus that represent amplified genes that have been moved from their chromosome of origin into the nuclear matrix. Double minutes can vary in size and number from cell to cell. The variability in number results from their unequal distribution following cell division. This occurs because double minutes do not contain centromeres or kinetochores and have no spindle attachment.

Homogeneously staining regions are relatively uniformly staining segments that represent incorporation of amplified genes on recognizable chromosomes. In most cancers, double minutes and homogeneously staining regions are associated with advanced disease and poor prognosis. In neuroblastoma, however, although not a primary change, gene amplification is not a late change and is usually present at the time of diagnosis.

5.1.4. Bladder Cancer Eighty-five to 95% of bladder cancers in the United States are transitional cell carcinomas arising from the transitional epithelium lining the bladder. Common primary changes in transitional cell carcinoma include trisomy 7, deletions involving 21q22, and deletions involving 10q22-24. The latter is the most commonly occurring structural change seen in transitional cell carcinoma.

Secondary cytogenetic changes include isochromosomes of the short arms of chromosomes 5 and 11 and the long arm of chromosome 11, deletions and translocations of 11p11-q11, deletions and translocations involving 1q21, and monosomy 9. Monosomy 9 is the most common cytogenetic change seen in transitional cell carcinoma. Deletions and rearrangements involving 13p14 are also seen and loss or inactivation of the Rb gene might be involved.

5.1.5. Small Cell Carcinoma of the Lung Of the four major types of lung cancer (adenocarcinoma, squamous cell carcinoma, small cell carcinoma and large-cell undifferentiated carcinoma), small cell lung cancer (SCLC) was the first to be characterized cytogenetically. SCLC is one of the most highly metastatic cancers in man.

A specific deletion of chromosome 3p14-p23 is seen in almost all cases of SCLC and is very specific to it. Trisomy 7 is also seen as a primary cytogenetic change. Trisomy 7 is not tumor-specific and is seen in many different tumors. It might not even be a malignancy-associated change, as it has been seen in benign cells around the lung cancer. Nevertheless, an extra chromosome 7 is often seen early in small cell cancer.

A variety of secondary changes might also be seen in SCLC. Most result in loss of heterozygosity of particular gene loci where known or suspected tumor suppressor genes reside. These include deletions of the long arms of chromosomes 5 (APC is located at 15q21-22) and 13 (Rb is located at 13q14), deletions of the short arms of chromosomes 9 and 17 (p53 is located at 17p13.1), and various deletions of chromosome 6. Gene amplification is also seen as a secondary change. These often involve the myc family genes and can take the form of double minutes or homogeneously staining regions. They are a late manifestation and are associated with poor prognosis.

5.1.6. Breast Cancer Breast cancer is very common in the United States and is the second leading cause of cancer deaths in US women. Primary cytogenetic changes include isochromosomes of the long arm of chromosome 1 and an unbalanced whole-arm translocation between chromosome 1 and 16. This results in the cells having two normal chromosomes 1, one normal chromosome 16, and a fourth chromosome consisting of the long arm of chromosome 1 and the short arm of chromosome 16. Monosomy 17 is another primary change seen in breast cancer. There are several cancer genes on chromosome 17 and loss of heterozygosity of chromosome 17 seems to play a role in some breast cancers.

There a large number of secondary changes that can be seen in breast cancer, including deletions of the short arm of chromosome 3, deletions of 6q21-22, trisomies of chromosomes 7, 18, and 20, and various rearrangements of chromosomes 1, 3, 7, and 11. Gene amplification is fairly common in breast cancer. It presents most frequently as double minutes, but homogeneously staining regions also occur. Gene amplification in breast cancer is more common in metastatic disease. Amplification of ERBB2, c-myc, and amplicons mapped to 11q13 and 20q13 have all been reported. A homogeneously staining region on the short arm of chromosome 8 is another recurrent example of gene amplification in breast cancer.

5.1.7. Colorectal Cancer Colorectal cancer is one of the leading causes of human morbidity and mortality. It is the fourth most frequently occurring cancer in the United States and the second leading cause of cancer deaths, surpassed only by lung cancer. The cytogenetics of colorectal cancers falls into two distinct categories: those characterized by polyploidy (specifically near-triploidy and near-tetraploidy) and those characterized by near-diploidy or pseudodiploidy (a chromosome count of 46 but with missing and extra chromosomes).

Those tumors that are near-triploid or near-tetraploid have complex karyotypes involving both numerical and structural abnormalities. These tumors tend to be poorly differentiated and are associated with short survival. By contrast, those that are near-diploid or pseudodiploid have simpler karyotypes involving primarily numerical abnormalities and unrelated clones. These tumors tend to be moderately to well differentiated and patient survival is longer.

Gains of chromosome 7 and 20 seem to be primary changes in colorectal cancer. An additional chromosome 7 has also been reported in benign adenomas of the colon, so although an early chromosomal change, it might not be a malignancy associated change per se.

A large number of recurrent secondary changes have been seen in colorectal cancer. These include isochromosomes of the long arms of chromosomes 1, 7, 8, 13, and 17. Isochromosome 17q results in loss of the p53 gene. Deletions of 1q13, the long arm of 12, and 17p11 are also reported. The latter again results in the loss of p53. Trisomies of chromosomes 8 and 12 also occur. Trisomy 12 results in their being an extra copy of the K-ras oncogene. Monosomy 18 results in loss of heterozygosity of DCC and other suppressor genes on 18q. Double minutes are seen in many colorectal cancers and are generally seen late in disease progression and carry a poor prognosis.

5.2. HEMATOLOGIC MALIGNANCIES Hematologic malignancies could be of myeloid or lymphoid origin. Those of myeloid origin include the myeloproliferative disorders (MPD's), the myelodysplastic syndromes (MDS's), and the acute myelogenous leukemias (AML's). Those of lymphoid origin include acute lymphocytic leukemia (ALL), the chronic lymphoproliferative disorders, and the lymphomas.

5.2.1. Myeloproliferative Disorders These are disorders that arise at the level of the pluripotent stem cell. Thus, all myeloid lineages are involved, although one predominates. There is overproduction of the three major cell lines in the bone marrow, giving rise to leukocytosis, thrombocytosis, and ery-throcytosis. The MPDs include chronic myelogenous leukemia (CML), essential thrombocytopenia (ET), polycythemia vera (PV) and myelofibrosis with myeloid metaplasia (MF/MM).

Chronic myelogenous leukemia (CML) represents 15-25% of all leukemias. It can occur in all age groups, but is most common in the fifth decade of life. CML is characterized by involvement of all three cell lineages, but overproduction of granulocytes is pronounced. The disease is characterized by three phases: (1) chronic, (2) accelerated, and (3) acute.

The chronic phase is relatively benign and lasts 3-5 yr. There is unregulated proliferation of the white cells, resulting in elevated white blood cell counts, but patients are often deceptively healthy in appearance. Fatigue, weight loss, and splenomegaly are sometimes seen. In the chronic phase, blood smears reveal a mixture of cell types. In the accelerated phase, the cells begin to lose their ability to differentiate and the peripheral white cell counts become even higher. In most cases, the disease enters an acute phase. This transformation can be gradual or rapid as the patient enters what is referred to as blast crisis. Increased numbers of immature cells, blasts, are seen in the bone marrow and usually the peripheral circulation. CML most often transforms to acute myelogenous leukemia (AML), subtypes M1, M2, and M4.

The primary cytogenetic change in CML is a balanced translocation between chromosomes 9 and 22 (t(9;22)(q34.1;q11.2)), the so-called Philadelphia translocation. This translocation brings together the c-ABL gene on chromosome 9 and BCR on chromosome 22 creating a hybrid gene the BCR-ABL fusion gene that is responsible for the disease. Most cases of CML will show the standard t(9;22) cytogenetically, but 10-15% will show a variant Philadelphia translocation involving additional chromosomes. Some cases show no cytogenetically visible translocation at all, although the gene rearrangement has taken place at the molecular level. For this reason, molecular techniques are considered the gold standard for diagnosing the

Philadelphia rearrangement. Cytogenetics still has a place in the management of patients with CML, however, as it will pick up secondary changes indicative of disease progression.

The Philadelphia rearrangement occurs early in tumor development and is the sole cytogenetic change early in the disease course. As the disease progresses, especially during the accelerated phase and blast crisis, additional chromosomal abnormalities appear and give rise to increasingly malignant subclones. The most frequently occurring secondary changes are the presence of a second Philadelphia chromosome, an extra chromosome 19, an extra chromosome 8, and an isochromosome of the long arm of chromosome 17. These additional changes can occur singly or in various combinations.

The other myeloproliferative disorders occur in older adults, generally after the age of 40. Essential thrombocytopenia is characterized by a marked increase of platelets in the peripheral circulation and megakaryocytes in the bone marrow. There is an overproduction of erythrocytes in polycythemia vera, and fibrosis of the bone marrow and extramedullary hematopoiesis characterize myelofibrosis with myeloid metaplasia. Fibrosis in the latter can make it difficult to obtain an adequate bone marrow sample.

Unlike CML, there are no specific chromosomal changes associated with the other myeloproliferative disorders. There are a variety of nonspecific changes that are seen with some frequency, however. These include deletions of the long arms of chromosome 13 and 20, monosomy 7, and tri-somy 8 and 9.

5.2.2. Myelodysplastic Syndromes Refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (REAB-T), and chronic myelomonocytic leukemia (CMML) comprise the myelodysplastic syndromes. All three major bone marrow cell lines are involved in the myelodysplastic sundromes (MDSs) because the malignant event occurs in the pluripotent stem cell or the myeloid progenitor cell. The MDSs exhibit hypercellu-larity of the bone marrow but lowered cell counts in the peripheral circulation. This occurs because there is an overproduction of cellular elements in the bone marrow, but their maturation is abnormal or dysplastic, and ineffective. Therefore patients, exhibit anemia, leucopenia, and/or thrombocytopenia. CMML leukemia is the exception to this. Patients with CMML have increased white blood cells and monocytes in both their bone marrow and peripheral circulation. The MDSs can evolve into acute leukemia.

Acquired cytogenetic abnormalities are seen in about 70% of cases of MDS. There are no chromosomal abnormalities specific to any of the MDSs, but cytogenetics can be useful in establishing the presence of a malignancy and differentiating it from benign conditions that also present with anemia, leukope-nia, and/or thrombocytopenia.

Deletions of the long arm of chromosome 5 are seen frequently in the MDSs. They could be seen as a sole change and generally carry a poor prognosis. Some of the other cytogenetic abnormalities seen in MDS include deletions of the long arm of chromosome 7 and monosomy of chromosome 5 and 7. Many other changes have also been reported.

5.2.3. Acute Myelogenous Leukemia Acute myeloge-nous leukemia can occur in any age group but is most common under one year and over 30 yrs of age. There is a marked increase after age 55-60. AML is characterized by a malignant accumulation of immature blast cells that replaces the normal cells of the bone marrow. Replacement of the normal cellular elements results in anemia, which causes fatigue and malaise, infections and fever, and bruising and hemorrhage. Patients with AML are usually sick when they present with the disease. The increased numbers of abnormal cells seen in CML are not the result of a proliferation but rather to a block in maturation of the cells and reduced rates of cell death.

The French-American-British (FAB) classification is one of many classification systems for AML. It categorizes AML into eight subtypes, M0-M7, based on cellular morphology and the differentiation pathway involved. Although the cytogenetic findings in some of the subgroups is nonspecific, it is very specific in others, and some findings have important prognostic value.

M0: Acute myelogenous leukemia without maturation. This is a malignancy of primitive blasts. There is no maturation of the cells and their origin as myeloblasts cannot be determined without use of electron microscopy or immunophenotyping. M0 represents less than 5% of AML cases. A variety of numerical and structural abnormalities can be seen in M0, but none is specific to it. A translocation, t(1;11)(p32;q23), has been reported in M0 and M5, and an inversion of the long arm of chromosome 3, inv(3) (q21q26), has been seen in M0 as well as most other AML subtypes.

M1: Acute myelogenous leukemia with minimal maturation. Blasts predominate in M1, but Auer rods might be seen. Auer rods are a fusion of cytoplasmic granules and are pathognomonic for cells of myeloid origin. This subtype accounts for about 20% of cases of AML. The cytogenetic findings of M1 are nonspecific and include trisomy 8, monosomy 7 and the inv(3)(q21q26) mentioned earlier. A translocation, t(3;3)(q21;q26), has been reported in M1 and several other AML subtypes.

M2: Acute myelogenous leukemia with maturation. This is the most common subtype of AML accounting for 30% of cases. Although immature cells prevail, Auer rods might be present and there is more maturation than in M1. A characteristic translocation, t(8;21)(q22;q22), is seen in 40% of cases of M2, and in 15% as the sole cytogenetic change. The translocation brings together ETO on chromosome 8 and AML1 on chromosome 21. Other cytogenetic changes include trisomy 8, trisomy 4, monosomy 7, and loss of the Y chromosome. The latter is seen as a secondary change, especially in men with the 8;21 translocation.

M3: Acute promyelocytic leukemia (APL). M3 is characterized by the presence of numerous primary granules and Auer rods. There is a hypergranular form in which the granules are very pronounced and a microgranular form in which the granules are less prominent. There is also a M3v variant in which the granules are not visible under light microscopy. Ten percent of AMLs are the M3 subtype. This is a slow-growing tumor. Direct cultures will often not reveal chromosomal abnormalities, so 24- and 48-h cultures are advised if APL is suspected.

Acute promyelocyte leukemia (APL) is characterized by a very specific translocation, t(15;17)(q22;q21.1), that is seen in over 90% of cases, but in no other cancer. The RARa gene that codes for retinoic acid is located at 17q21.1 and this translocation brings it together with the PML gene located at 15q22, creating the PML/RARa fusion gene.

Chemotherapy alone cannot be used to treat APL because it lyses the promyelocytes. This releases the cell contents, which disrupts coagulation and can result in fatal diffuse bleeding. To overcome this problem, all-trans-retinoic acid (ATRA) is administered prior to the chemotherapy. ATRA is a vitamin A analog that matures the promyelocytes to polymorphonuclear leukocytes, thus avoiding the potentially fatal sequela.

M4: Acute myelomonocytic leukemia (AMML). This leukemia is a mixture of monocytic and granulocytic cells. There is a variant, M4 with eosinophilia (M4eo), in which eosinophils predominate. M4 represents about 25% of AMLs. An inversion, inv(16)(p13q22), is seen in 30% of M4eo and occasionally with other subtypes of AML. The inversion brings together MYH11 at 16p13 and CBFfi at 16q22, creating the CBF/3/MYH11 fusion gene that has transforming ability. This is a clinically significant finding, as patients with the inverted 16 have a good prognosis, especially when treated with cytosine-arabinoside. Other cytogenetic changes include a deletion of 16q22, also seen in M4eo, trisomy 8, and monosomy 7. An additional chromosome 22 is sometimes seen in conjunction with the inverted 16.

M5: Acute monoblastic leukemia (AMoL). About 10% of AMLs are M5. M5a is characterized greater by than 80% immature monoblasts, whereas M5b has greater than 20% more mature monoblasts. A variety of structural abnormalities involving the 11q23 breakpoint have been described in M5, including t(9;11)(p22;q23), t(11;17)(q23;q21), t(11;17)(q23;q23), t(11;19)(q23;p13.3), and t(11;19)(q23;p13.1). The MLL gene is located at 11q23 and appears to be involved in the creation of fusion genes in the various rearrangements. The t(9;11) is subtle, involving an exchange of very similar segments and could therefore be under recognized. The 9; 11 translocation occurs most frequently in the M5a subtype. Trisomy 8 is also seen in M5.

M6: Acute erythroleukemia (AEL). Fewer than 5% of AMLs are the M6 subtype. The neoplasm consists of myeloblasts and erythroblasts. The inversion, inv(3)(q21q26), has been reported in M6 and most other AML subtypes. A translocation, t(3;5)(q25;q34), and the nonspecific finding of monosomy 7 and trisomy 8 has also been reported in M6.

M7: Acute megakaryocytic leukemia. M7 accounts for less than 5% of all AMLs. It is characterized by megakaryocytes and myelofibrosis. As with other conditions involving myelofi-brosis, the fibrosis can make it difficult to obtain a good cytogenetic sample. A number of structural rearrangements have been reported in M7, but most are nonspecific and are seen in a number of other AML subtypes as well. The exception is a translocation, t(1;22)(p13;q13). This rearrangement is seen especially in infants and children and is the most common abnormality seen in young children with M7.

5.2.4. Acute Lymphocytic Leukemia Acute lymphocytic leukemia (ALL) is a malignant proliferation of immature lym-phoid in the bone marrow and usually the peripheral circulation. Peripheral blood studies reveal anemia, thrombocytopenia, and usually increased numbers of lymphoblasts. Most cases are of B-cell origin, so use of a B-cell mitogen is recommended by some.

Acute lymphocytic leukemia can occur at any age, but is seen most often in children age 1-10 yr, with most cases occurring between 3 and 5 yr. Symptoms of ALL include fatigue, bruising, hemorrhage, bone pain (especially in younger patients), and neurologic symptoms if there has been involvement of the central nervous system.

Chromosomes from ALL often exhibit poor quality and poor staining, making them diagnostically challenging. Nevertheless, about two-thirds of cases of ALL demonstrate recognizable cytogenetic changes, and the cytogenetic findings often have prognostic significance.

Hyperdiploidy is seen in 25-30% of childhood ALL, but only 10% of adult ALL. Massive hyperdiploidy (a chromosome number of greater than 50), and especially the occurrence of 54-57 chromosomes without structural anomalies, carries a good prognosis and has the best prognosis of all cytogenetic abnormalities in ALL. Hyperdiploidy of 47-50 chromosomes and pseudodiploidy have an intermediate prognosis.

Near-haploidy (a chromosome number of less than 30 and usually 23-28) is associated with a generally poor outcome. It is important not to overlook apparently broken metaphase spreads when performing the cytogenetic evaluation, as they could represent near-haploid cells.

A variety of structural abnormalities could be seen in ALL. Almost all carry a poor prognosis. A translocation, t(9;22)(q34.1;q11), looks cytogenetically like the one seen in CML, but the breakpoint on the chromosome 22 is slightly different at the molecular level. This translocation is associated with an extremely poor prognosis and is seen more frequently as patient age increases. A translocation, t(4;11)(q21;q23), is seen in infants with ALL and also carries a poor prognosis. When seen in older patients, it is usually associated with prior exposure to genotoxic agents. Rearrangements involving 11q23 are common in treatment-related leukemias. In this translocation, MLL, located at 11q23, and AF4, located at 4q21, are fused, producing a new transcription factor.

There is one rearrangement seen in pediatric ALL that carries a good prognosis. This is the translocation t(12;21) (p13;q22). It creates a fusion between AML1 at 21q22 and TEL at 12p13. This translocation cannot be visualized cytogenetically, but it can be identified with FISH probes that detect the fusion of these two genes.

Translocations involving a 14q11 breakpoint are seen with some frequency in T-cell ALL. Some examples are t(10;14) (q24;q11), t(11;14)(p13-15;q11), and t(8;14)(q24;q11). The T-cell receptor-a (TCRA) locus resides at 14q11 and it appears that juxtaposition of it with a variety of oncogenes activates those oncogenes. In general, T-cell ALL patients have a poorer prognosis than patients with B-cell ALL.

5.2.5. Chronic Lymphoproliferative Disorders Of the many chronic lymphoproliferative disorders, only two, chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), will be addressed here.

Chronic lymphocytic leukemia represents about 30% of all leukemias in the United States and Europe and is the most commonly occurring leukemia in these populations. CLL is a disease of middle-aged and elderly adults. It is rare before the fifth decade. Many patients are asymptomatic when they are diagnosed with the disease, but others present with lym-phadenopathy or splenomegaly. The peripheral blood shows increased numbers of white blood cells with mature lymphocytes predominating. For this reason, peripheral blood samples are often adequate for detecting chromosomal abnormalities associated with CLL. CLL has a low mitotic rate, so culture intervals of 5-7 d are generally recommended rather than the standard direct or 24-hr cultures that give best result for most leukemias.

Over 95% of CLLs are of B-cell origin, so use of a B-cell mitogen is generally recommended. Although T-cell CLL is relatively uncommon, patients with the chromosome instability syndrome ataxia telangiectasia have an increased incidence of it. B-Cell CLL has a good prognosis, whereas T-cell CLL carries a poor prognosis. CLL can transform, becoming an acute leukemia, most often ALL.

Trisomy 12 is the most commonly encountered cytogenetic change in B-cell CLL, being seen in about one-third of cases. The translocation t(11;14)(q13;q32) is the most common translocation seen in B-cell CLL, and other rearrangements involving chromosome 14 also occur. Deletions and translocations involving the long arm of chromosome 13 are seen fairly frequently.

The inversion inv(14)(q11q32) is commonly seen in T-cell CLL as are other rearrangements involving q11 and q32 breakpoints on chromosome 14. As mentioned previously, the TCRA locus is located at 14q11.

Multiple myeloma is a B-cell tumor in which there is a malignant proliferation of plasma cells that impairs bone marrow function. The abnormal cells produce monoclonal immunoglobulin with excess light chains. MM is also characterized by lytic bone lesions and impaired renal function resulting from excretion of the surplus light chains (Bence-Jones proteins). Patients with MM might bone pain and fractures, anemia and fatigue, and excessive urination and thirst. X-rays might demonstrate the lytic bone lesions.

Plasma cells divide slowly. As a result, the majority of cells in cytogenetic preparations might represent normal bone marrow components. Obviously, these will not show chromosomal abnormalities that might be present in the abnormal plasma cells. Analysis of large numbers of cells is often necessary to improve the likelihood that the appropriate cells are being detected. FISH can be helpful by allowing large numbers of cells to be screened.

Thirty to fifty percent of cases show cytogenetic changes, and of these, one-quarter involve abnormalities of chromosome 14. A third of these are a translocation, t(11;14)(q13;q32). The IgH gene is located at 14q32.22 and BCL1 is located at 11q13. The juxtaposition of the two genes activates BCL1. Twenty percent of cases with a chromosomal abnormality show rearrangements of chromosome 11. Half of these are the t(11;14) just mentioned. This translocation is generally seen with mono-

somy 13, deletions of the long arm of chromosome 13, or abnormalities of chromosome 1. Abnormalities of chromosome 1 are seem in 40% of cases with a cytogenetic change. Deletions of the long arm of chromosome 6 are seen in 15% of cases and hyperdiploidy is seen in two-thirds of chromosomally abnormal cases.

5.2.6. Lymphomas Lymphomas can be broadly classifies as Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Hodgkin lymphoma is the most common lymphoma. It occurs in young people and is seen more frequently in males than females. Patients often present with lymph node enlargement, but might also experience fever or weight loss.

A large binucleated cell, the Reed-Sternberg cell, characterizes Hodgkin lymphoma cytologically. This is thought to be the malignant cells of Hodgkin lymphoma, but only comprises about 5% of the tumor. The majority of the tumor, 95%, consists of benign histiocytes, lymphocytes, eosinophils, and plasma cells. Because of the large numbers of benign cells present in this tumor, a standard cytogenetic study could reveal few if any malignant cells. For this reason, a large number of cells must be evaluated to provide meaningful information.

Many structural abnormalities have been seen in Hodgkin lymphoma, with rearrangements involving chromosome 1 being seen in about a third of cases. Other anomalies include additional material on the long arm of chromosome 14, deletions of the long arm of chromosome 6, isochromosomes of the short arm of chromosome 6, and abnormalities involving the long arms of chromosomes 3 and 7 and the short arms of chromosomes 12 and 13. Trisomies of chromosomes 1, 3, 7, 8, and 21 are the most commonly occurring numerical abnormalities.

Non Hodgkin lymphoma is a complex group of neoplasms that over the years has been classified in numerous ways. Cytogenetic abnormalities are seen in 90% of cases, far greater than in any leukemia. The cytogenetics is often very complex, and this, combined with the confusing classification of NHL, has made comprehension of the karyotypic findings difficult. One NHL, Burkitt's lymphoma, does show highly specific and consist cytogenetic changes, however.

Burkitt lymphoma is a an immunoglobulin (Ig) producing, B-cell tumor. The Epstein-Barr virus might play a role in its development. Burkitt's lymphoma occurs endemically in Africa and nonendemically in other parts of the world.

Eighty percent of cases of Burkitt lymphoma show a specific translocation, t(8;14)(q24;q32). The remaining 20% show one of two variant translocations. Two thirds of these show t(8;22)(q24;q11) and the remaining one-third show t(2;8) (p11;q24). What these translocations have in common is an 8q24 breakpoint. The c-myc oncogene is located at this breakpoint and the genes for the Ig heavy chain, kappa light chain, and lambda light chain reside at 14q32, 2q24, and 22q11, respectively. c-myc translation appears to be activated by the juxtaposition of the oncogene next to the Ig heavy, kappa light chain, or lambda light chain genes.

A number of other nonrandom structural and numerical abnormalities have been observed in Burkitt lymphoma. Secondary changes include abnormalities of the short arm of chromosome 1, seen in 30% of cases, and abnormalities involving a 13q34 breakpoint, seen in 15% of cases.

5.2.7. Treatment-Related Hematologic Disorders Over the years, there has been prolonged survival and even cure of cancer patients because of better methods of treatment, especially involving radiation and chemotherapy. Sometimes, these treatments induce new malignancies, often treatment-related myelodysplastic disorders and AMLs (t-MDS and t-AML).

Hypodiploidy (fewer than 46 chromosomes) is seen in over half of such cases. Monosomy 7 is seen in half of cases and monosomy 5 is present in 20-25% of cases. Deletions of the long arm of chromosomes 7 and 5 are also fairly common. Patients who have received topoisomerase II inhibitors as part of their treatment frequently show balanced rearrangements involving 11q23 and 21q22 (MLL and AML1 are located at these breakpoints, respectively), the inverted 16 characteristic of AML M4eo and the translocation t(15;17), typical of AML M3.

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  • michael theissen
    What is acquired abnormalities?
    2 years ago
  • Mattie
    What is acquired chromosomes?
    1 year ago

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