Lecture 12: Cancer Cytogenetics (January 7, 2025) PDF

LECTURE 12: CANCER CYTOGENETICS Ts. DR. MOHD FADLY MD AHID 7th JANUARY 2025  Problems of Spontaneous early growth & abortion Fertility development problems CLINICAL CYTOGENETICS Family Cancer history...

LECTURE 12: CANCER CYTOGENETICS Ts. DR. MOHD FADLY MD AHID 7th JANUARY 2025  Problems of Spontaneous early growth & abortion Fertility development problems CLINICAL CYTOGENETICS Family Cancer history Pregnancy in a woman ≥ 35 years CANCER CYTOGENETICS Chromosome analysis is one of the first approaches to genetic testing and remains a key component of genetic analysis of constitutional and somatic genetic disorders (cancer). Cytogenetics is important to delineate the chromosomal changes in specific forms of cancer and the relation of breakpoints of the various structural rearrangements to oncogenes. CANCER CYTOGENETICS The cytogenetic changes in cancer cells are numerous & diverse; many are repeatedly seen in the same type of tumour. Cytogenetics as an important tool for diagnostic & prognosis of cancer. Cytogenetics in Hematological Malignancies Chromosome analysis has become a critical aspect in the workup of hematopoietic neoplasm. Most patients with hematological malignancies have clonal chromosomal abnormalities. The pattern of chromosomal aberrationsmay predict treatment response and clinical outcome and is good for risk stratification. Genes located at the breakpoints of the recurrent abnormalities play an important role in the process of tumorigenesis and can be the target oftreatment.  HematologicalMalignancy Included lymphoma and leukemia Leukemia: a malignancy (cancer) of the blood cells /bone marrow Lymphomas: Malignancies of lymphatic system (lymph nodes) lose their ability to differentiate Increase in cell growth and proliferation An immature state-outgrow, causes failure of the hematopoietic system and ultimately invading other organs  Etiology Uknown Oncogene mutation /tumor suppression genealteration Host factors – Congenital chromosomal abnormalities (e.g: increased frequency in down syndrometo acute leukemia) – Chromosomal abnormalities / gene rearrangements – Hereditary Immunodeficiency state (ataxia-telangiectasia and sex- linked agamaglobulinemia) Environmental factors – Ionizing radiation (e.g: exposure to nuclear weapons in Hiroshima and Nagasaki-ALL, AML AND CML) – Chemicals (e.g: Benzene) – Drugs (e.g:Cytotoxic alkylating chemotherapeutic agents) – Viruses (e.g: Human T-cell leukemia-lymphoma virus-I, HTLV-I causative of T-cell leukemia- lymphoma; HTLV-II-atypical hairy cell leukemia; Epstein’s Bar virus has been related to Burkitt’s lymphoma)  Incidence Frequent in adults than children(10:1) Increase incidence in males than females(1-2:1) Heerema, N. A. (2017). The AGT Cytogenetics Laboratory Manual, 499–575. Classification of hematologic malignancies cell type (e.g: myeloid /lymphoid) different cells of origin, giving rise to the different types of leukaemia onset and progression (e.g: acute/ Chronic) the speed of the outgrowing population of cancer cells Classification of hematologic malignancies Classification of hematologic malignancies  Recurrent chromosomal aberrationsin hematological malignancies Some recurrent chromosomal abnormalitiesare tumor- and even subtype-specific, so are good for diagnosis and classification.  Useful 1. Diagnosis, prognosis and classification 2. Risk stratification 3. Selection of proper treatment / potentialof treatment advance 4. Follow-up of the response / Monitoring effect of treament Diagnosis Bone marrow smears from patients presented with pancytopenia with multilineage dysplasia (hypoplastic features) Diagnosis: Myelodysplastic Syndromes (MDS) Some cases of MDS, particularly Refractory anaemia, are difficult to diagnose by morphologic criteria alone. Karyotype: 46,XY,-7 Diagnosis: MDS Monosomy 7 as clonal acquired chromosomal abnormality have a poor outcome Risk Stratification  Impact of cytogenetic inAML (WHO 2016 classification) The World Health Organization (WHO) system divides AML into several groups:  Acute Myeloid Leukaemia(AML) AML is heterogeneous group of disorders at the cytogenetic and molecular geneticslevels. Clonal chromosomal abnormalities are seen in about 50-60% of patients with newly diagnosed AML. Normal karyotype (NK) which comprises approximately 33– 50% of AML. Several specific recurrent chromosome aberrations have been described in AML e.g. t(8;21) (q22;q22), t(15;17)(q22;q11-12), inv(16)(p13q22),are specific for distinct subgroups. Cytogenetic risk group in AML  Impact of cytogenetic inAML Favorable unfavorable M.L. Smith et al. / Blood Reviews 25 (2011) 39–51  Myelodysplastic syndromes (MDS) Myelodysplastic syndromes (MDS) MDS subtypesinclude: are a group of heterogeneous clonal hematopoietic stem cell disorders the presence of dysplastic changes in one or more of the hematopoietic lineages (multilineage). The WHO divides myelodysplastic syndromes into subtypes based on the type of blood cells involved — red cells, white cells and platelets Malcovati, L., & Nimer, S. D. (2008). Cancer Control, 15(4_suppl), 4–13. Recurrent cytogenetic abnormalities in MDS Refractory anemia Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Ring sideroblasts and multilineage dysplasia (RCMD-RS) Myelodysplastic syndrome with excess blasts — types 1 and 2 (RAEB-1 & RAEB-2) MDS with isolated del5q Malcovati, L., & Nimer, S. D. (2008). Cancer Control, 15(4_suppl), 4–13. Recurrent cytogenetic abnormalities in MDS Cytogenetic prognostic scoring system inMDS n=2754 MDS  n=131 MDS patients with del(5q) 5q- patients have previously been well defined as having relatively good prognosis in MDS; poor prognosis was indicated when it was combined with other anomalies. Tasaka 2008 Leukemia 22, 1874–1881 (2008). https://doi.org/10.1038/leu.2008.199  Impact of cytogenetic inALL (WHO 2016classification) The World Health Organization (WHO) system divides ALL into several groups: Acute lymphoblastic leukemia(ALL) Clare, N., & Hansen, K. (1994). Hematology /Oncology clinics of North America, 8(4): 785-807  Hyperdiploidy. Karyotype: 54,XX,+X,+4,+6,+10,+14,+17,+21,+21 High hyperdiploidy (>50 chromosomes) occurs in about 25% of paediatric cases typically is associated with a good outcome; may be attributed to the presence of specific extra chromosomes: 4, 10 and 17 predicted a good outcome Heerema, N. A. (2017). The AGT Cytogenetics Laboratory Manual, 499–575.  Near‐haploid ALL. Karyotype: 25,X,+14,+21. Hypodiploidy with 44 or 45 chromosomes has an intermediate prognosis Hypodiploidy with ≤43 chromosomes has a very poor outcome Heerema, N. A. (2017). The AGT Cytogenetics Laboratory Manual, 499–575.  Multiple myeloma(MM) It is a plasma cell neoplasm, resulting from proliferation of immuno- secretory plasma cells. It occurs primarily in middle‐age to elderly patients and affects African Americans more often thanwhites At diagnosis 15–30% of patients are asymptomatic Symptomatic – include weakness and fatigue, – bone pain, – demonstrable monoclonal protein in serum or urine, decreased normal immunoglobulin, – anemia, – hyperuricemia, – bone marrow plasmacytosis,etc  Impact of genomic aberrationsin multiple myeloma Cytogenetics are a primary risk factor in multiple myeloma. Good risk cytogenetics includes hyperdiploidy with 48‐74 chromosomes. – The extra chromosomes are the “odd numbered” chromosomes, 3, 5, 7, 9, 11, 15, 19 and 21.  Impact of genomic aberrations on OS in multiple myeloma Poor prognostic features del(17p) del(13q) t(4;14) Overall Survival (OS) Blood (2007)109 (8):3489–3495 Chronic lymphocytic leukemia(CLL) It is a B‐cellneoplasm The most frequent adult leukemia, in middle‐age to elderly patients, and not inchildren; comprising up to 30% of all adult leukemias There is a malepredominance. Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression andsurvival. These findings have implications for the design of risk-adapted treatment strategies.  Median survival times sole abnormality months 17p deletion 32 11q deletion 79 12q trisomy 114 normal karyotype 111 13q deletion 133 Dohner H et al., N Engl J Med. 2000; 343:1910-6. Follow-up of clinical course Chronic myeloid leukemia (CML) Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), creating a derivative 9q+ and a shortened 22q-. The latter is known as the Philadelphia chromosome. The t(9;22) is present in 90% to 100% of cells analyzed and has been demonstrated in the myeloid, erythroid, and megakaryocytic cell lines. Chronic myeloid leukemia (CML) Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and ponatinib Progression of CML from chronic phase to accelerated phase or blast crisis is often associated with secondary chromosomal aberrations.  t(9;22) /BCR-ABL1 CML, ALL & AML ALL: detected in adult (up to 30%) and children(2- 5%) ; rarely in AML (