Cyto PPTS.pdf

Cancer Cytogenetics Miguel Lorenz C. Parawan, RMT, CSSWB Lesson Objectives: By the end of this session, students will be able to: Familiarize the etymology, as well as the history of cancer genetics; Analyze karyotypes related to neoplasms and tumors; Observe proper nomenclature in cancer kary...

Cancer Cytogenetics Miguel Lorenz C. Parawan, RMT, CSSWB Lesson Objectives: By the end of this session, students will be able to: Familiarize the etymology, as well as the history of cancer genetics; Analyze karyotypes related to neoplasms and tumors; Observe proper nomenclature in cancer karyotyping; Identify the affected gene(s) in cancer genetics; Understand the risk factors in developing cancer; Learn the different hematologic neoplasms and solid tumors; Correlate cancer to its chromosomal aberrations. HISTORY OF CANCER GENETICS Comes from the Greek words: ○ neo = new ○ plasma = growth Zur Frage der Entstehung maligner Tumoren (On the Problem of Origin of Malignant Tumors) by Theodor Heinrich Boveri is probably the most important early contribution on the genetics of cancer, as it offered some of the concepts still applicable today, specifically that chromosome imbalances, mitotic disturbance, and monoclonality are all attributes found in cancer cells. HISTORY OF CANCER GENETICS A milestone of this investigation occurred in 1960 with the publication of the first article by Peter Nowell and David Hungerford on the association of chronic myelogenous leukemia with a small size chromosome, known today as the Philadelphia (Ph) chromosome. CANCER CYTOGENETICS HEMATOLOGIC NEOPLASMS Myeloid Neoplasms Lymphoid Neoplasms SOLID TUMORS Myeloid Neoplasms Myelodysplastic Syndromes (MDS) Myeloproliferative Neoplasms (MPNs) ○ Chronic Myelogenous Leukemia ○ Polycythemia Vera ○ Primary Myelofibrosis ○ Essential Thrombocythemia Acute Myeloid Leukemia (AML) Lymphoid Neoplasms Acute Lymphoid Neoplasms ○ Acute T-Cell Lymphoblastic Leukemia Mature B-Cell Neoplasms ○ Non-Hodgkin Lymphoma ○ Hodgkin Lymphoma ○ Burkitt Lymphoma ○ Hairy Cell Leukemia (Typical and Variant) ○ Plasma Cell Myeloma Lymphoid Neoplasms Mature T-Cell Neoplasms ○ Natural Killer Cell Leukemia ○ Adult T-Cell Leukemia/Lymphoma ○ Mycosis Fungoides ○ Sézary Syndrome Solid Tumors Central Nervous Tumors ○ Gliomas ○ Astrocytomas ○ Oligodendroglial Tumors Gastrointestinal Tumors ○ Liver Tumors ○ Salivary Gland Tumors ○ Dermal Tumors Solid Tumors Genitourinary Tumors ○ Renal Cell Carcinoma ○ Wilms Tumor ○ Prostate Cancer ○ Bladder Cancer Epithelial Cancer ○ Breast Cancer ○ Lung Cancer Solid Tumors Bone and Soft Tissue Tumors ○ Lipoma ○ Liposarcoma ○ Osteosarcoma CANCER KARYOTYPE NOMENCLATURE TERMINOLOGY Terms used exclusively in neoplasia nomenclature include: Clone Mainline Stemline Sideline Composite karyotype; and Unrelated clones TERMINOLOGY 1. CLONE: A cell population derived from a progenitor cell; constitutes at least 2 mitotic cells with the same chromosome gain or structural aberration, and mitotic cells with the same chromosome loss. 2. STEMLINE (sl): The most basic clone of a tumor cell population and is always written first in the nomenclature string. TERMINOLOGY 1. S 2. 3. SIDELINES (sdl): Are additional related clones or sub-clones; follows the stemline and written in increasing complexity; use “idem” to refer back to the stemline only; Use sdl1, sdl2, sdl3, etc. to refer back to the stemline and previous sideline. 4. MAINLINE (ml): The largest clone in a tumor; may or may not be the stemline. TERMINOLOGY Marker chromosome: A structurally abnormal, unidentified extra piece of chromosomal material, usually occurring in addition to the normal chromosome complement. Also referred to as supernumerary chromosomes. Ring chromosome: Arise following breakage and fusion at the telomeric or distal regions of both chromosome arms. TERMINOLOGY Double-minute chromosome: circular fragments of DNA whose presence is associated with the onset of certain cancers. They are lethal, as they are highly amplified and typically contain oncogenes. ORDER OF LISTED ABERRATIONS When naming aberrant chromosomes, particularly in cancer cytogenetics, the following lists down the order of nomenclature: 1. Total number of chromosomes 2. Sex chromosomes 3. Numerical abnormal autosome 4. Structural abnormal autosome 5. Markers and rings (mar, r) 6. Double-minute Chromosomes (dmin)  CANCER KARYOTYPE 46,XY,t(8;14)(q24.1;q32)/47,XY,t(8;14)(q24.1;q32),+der(14)t(8;14)(q24.1;q32) CLONE 1 CLONE 2 / SIDELINE 1 Description: A clone (stemline) with 46 chromosomes and an (8;14) translocation in 20 cells, with a subclone of six cells with 47 chromosomes showing the t(8;14) and gain of a derivative chromosome 14 resulting from the t(8;14). Stemline: CLONE 1 Mainline: CLONE 1 Sideline: CLONE 2  CANCER KARYOTYPE CLONE 3 / SIDELINE 2 46,XY,t(8;14)(q24.1;q32)/45,sl,-X/46,sdl1,+8/47,sdl2,+der(14)t(8;14) CLONE 1 CLONE 2 / SIDELINE 1 CLONE 4 / SIDELINE 3 Description: The example shows a male karyotype with t(8;14) as the sole abnormality. Three subclones/sidelines are present. Sideline 1 is the mainline with the same abnormality with the stemline, but with loss of chromosome X. Sideline 2 has the same abnormality with the stemline and sideline 1, but with extra chromosome 8. Finally, sideline 3, has the same abnormality with the stemline and sideline 2, and a derivative chromosome 14. Stemline: CLONE 1 Mainline: CLONE 2 Sideline: CLONE 2,3,4 CYTOGENETICS OF MYELOID NEOPLASMS Myelodysplastic Syndromes (MDS) Myeloproliferative Neoplasms (MPNs) Acute Myeloid Leukemia (AML) MYELODYSPLASTIC SYNDROMES The term myelodysplastic syndrome (MDS) refers to heterogeneous group of hematopoietic stem cell neoplasms characterized by a series of similar features such as dysplastic cellular morphology, defect in cellular maturation, and increased risk of transformation into acute myeloid leukemia (AML). They are group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. MYELODYSPLASTIC SYNDROMES MDS with Deletion of 5q ○ The critical deleted region is approximately 1.5 Mb in size and is located at 5q31.2, where the EGR1 gene is located. del(5q) can be associated with the so-called 5q− syndrome. MDS patients are placed in the most favorable prognostic category. MYELODYSPLASTIC SYNDROMES MDS with Deletion of 7q or Monosomy 7 ○ Three regions are most frequently deleted: 7q22, 7q31.1, and 7q31.3. ○ Deletion of 7q/monosomy 7 has been viewed as a marker of poor prognostic outcome. MYELODYSPLASTIC SYNDROMES MDS with Trisomy 8 ○ Gain of one copy of chromosome 8 is recurrent in all myeloid neoplasms. ○ Trisomy 8 is often present as an additional abnormality, particularly in addition to del(5q). ○ These patients are given a high prognostic risk MYELOPROLIFERATIVE NEOPLASMS Myeloproliferative neoplasms (MPNs) are stem cell disorders characterized by proliferation of one or more myeloid cellular elements in the marrow and mostly affect adult individuals. CLASSIC MPNs NON-CLASSIC MPNs Chronic Myelogenous Leukemia (CML) Chronic Eosinophilic Leukemia (CEL) Polycythemia Vera (PV) Systemic Mastocytosis Primary Myelofibrosis (PMF) Chronic Neutrophilic Leukemia (CNL) Essential Thrombocythemia (ET) MYELOPROLIFERATIVE NEOPLASMS The classic MPN exhibits similar cytogenetic abnormalities, such as gain of 1q, +8, +9, del(13q), and/or del(20q). Philadelphia (Ph) chromosome translocation—characterized by the presence of the t(9;22) (q34;q11.2) notably seen in CML. MYELOPROLIFERATIVE NEOPLASMS Chronic Myelogenous Leukemia ○ A stem cell neoplasm that can occur at any age but is most frequent in the 5th and 6th decades of life. ○ CML is characterized by the t(9;22)(q34;q11.2), which leads to the formation of a chimeric transcript between the ABL1 and BCR genes at 9q34 and 22q11.2, respectively. ○ The derivative chromosome 22 is also known as the Philadelphia (Ph) chromosome and is the first abnormality to have been associated with a specific malignant neoplasm. MYELODYSPLASTIC SYNDROMES MYELOPROLIFERATIVE NEOPLASMS Polycythemia Vera (PV) ○ Polycythemia vera (PV) is a myeloproliferative neoplasm of adults (50–60 years of age) characterized by a proliferation of red blood cells, which in some patients leads to bleeding and thrombosis. ○ At the chromosome level, patients are BCR-ABL1 fusion-negative, and most, if not all, cases have a mutation at codon 617 in the Janus kinase 2 gene (JAK2, located at 9p24.1). ○ The most common abnormalities during disease progression are del(5q), del(7q), and/or del(17p). MYELOPROLIFERATIVE NEOPLASMS MYELOPROLIFERATIVE NEOPLASMS Primary Myelofibrosis (PMF) ○ Also known as idiopathic myelofibrosis and agnogenic myeloid metaplasia. ○ Characterized by marrow fibrosis with an increased number of megakaryocytes and immature granulocytes and associated anemia. ○ Affected patients are generally in their 5th and 6th decade of life. ○ Approximately 50% of patients with PMF have the JAK2 V617F mutation, but unlike PV, no mutations of JAK2 other than V617F have been found. MYELOPROLIFERATIVE NEOPLASMS MYELOPROLIFERATIVE NEOPLASMS Essential Thrombocythemia (ET) ○ Essential thrombocythemia (ET) is associated with an increased number of platelets and megakaryocytes, plus fibrosis in the marrow. ○ Similar to the other classic MPN, JAK2 mutations are also detected in these patients. ○ Approximately 50% have the characteristic JAK2 V617F mutation found in PV and MPF. MYELOPROLIFERATIVE NEOPLASMS +8, +9, del(13q), and del(20q) are the most common. Gain of 1q, del(5q), and del(7q) may also be seen. MYELOPROLIFERATIVE NEOPLASMS Acute Myeloid Leukemia (AML) ○ Acute myeloid leukemia (AML) is defined by the presence of myeloblasts in the bone marrow, peripheral blood, and other tissues. ○ At least 20% blasts should be present in the marrow. ○ Although AML more frequently affects adults in their 6th decade of life, it has been described in children and young adults as well. MYELOPROLIFERATIVE NEOPLASMS AML with t(8;21)(q22;q22.3) ○ The t(8;21) leads to a RUNX1- RUNXT1 (formerly AML1-ETO) fusion and is generally associated with a favorable prognostic outcome. ○ AML with maturation and as subtype M2 according to the FAB classification. MYELOPROLIFERATIVE NEOPLASMS AML with inv(16)(p13.1q22.1) or t(16;16)(p13.1;q22.1) ○ Presence of myelomonocytic blasts and atypical eosinophils. ○ AML M4 EO in the FAB classification, and generally associated with a favorable prognostic outcome. ○ Abnormality leads to the fusion of MYH11 at 16p13.1 with CBFB at 16q22.1 MYELOPROLIFERATIVE NEOPLASMS AML with inv(16)(p13.1q22.1) or t(16;16)(p13.1;q22.1) MYELOPROLIFERATIVE NEOPLASMS Acute Promyelocytic Leukemia with t(15;17) (q24.1;q21.2) ○ The formation of this translocation leads to a fusion between PML at 15q24.1 and RARA at 17q21.2. ○ Due to the high risk of early death and the potential for high cure rate, it is essential to immediately identify this leukemia. CYTOGENETICS OF LYMPHOID NEOPLASMS Mature B-Cell Neoplasms Mature T-Cell Neoplasms MATURE B-CELL NEOPLASMS Non-Hodgkin Lymphoma ○ Heterogeneous group of disorders characterized by localized proliferation of lymphocytes. ○ Most NHL cases are of B-cell origin and are characterized by rearrangements involving the immunoglobulin genes: IGH@ at 14q32.3 IGK@ at 2p12, and IGL@ at 22q11.2 MATURE B-CELL NEOPLASMS Hodgkin Lymphoma ○ Hodgkin lymphoma (HL) is an indolent neoplasm of the lymphatic system that makes up approximately 30% of all lymphoma cases. ○ The most notable morphologic characteristics of HL is the presence of giant cells called Reed-Sternberg cells. ○ HL is subdivided into two morphologically and clinically distinct subgroups: nodular and classic. CHL accounts for about 95% of all Hodgkin lymphomas and is therefore the most common type analyzed. MATURE B-CELL NEOPLASMS MATURE B-CELL NEOPLASMS Burkitt’s Lymphoma ○ Three immunoglobulin gene translocations, all affecting MYC at 8q24.2, are seen in BL. The most common of these, t(8;14)(q24.2;q32.3), is detected in about 75–80% of patients. ○ All three translocations involve MYC and one of the three immunoglobulin genes: IGH@ at 14q32.3 IGK@ at 2p12 IGL@ at 22q11.2 MATURE B-CELL NEOPLASMS Burkitt’s Lymphoma Partial karyograms illustrating the three translocations involving MYC (at 8q24.2) in Burkitt lymphoma. In these translocations, the relocation of MYC to the immunoglobulins IGK@ , IGH@ , and IGL@ loci, located at 2p12, 14q32.3, and 22q11.2, respectively, leads to its overexpression. MATURE B-CELL NEOPLASMS Hairy Cell Leukemia ○ Hairy cell leukemia (HCL) is an indolent mature B-cell lymphoproliferative neoplasm that affects adult individuals aged 50 years and over. ○ The circulating B-lymphocytes are small to medium in size and have a characteristic morphology with prominent cytoplasmic projections termed hairs. ○ Notably results from BRAF V600E mutation. The BRAF gene is located on 7q34, a chromosome region often implicated in HCL. MATURE B-CELL NEOPLASMS Plasma Cell Myeloma (Multiple Myeloma) ○ Plasma cell myeloma (PCM), is a neoplasm that affects the terminally differentiated plasma cells in the bone marrow. ○ Translocations involving chromosome 14, specifically 14q32.3 (IGH@), are seen in approximately 85% of the cases. ○ Associated with an unfavorable prognosis. MATURE B-CELL NEOPLASMS Hypodiploid karyogram in a patient with high-risk plasma cell myeloma showing, among other abnormalities, the simultaneous loss of chromosomes 13, 14, and 17. MATURE T-CELL NEOPLASMS Natural Killer Cell Lymphoma (NKCL) ○ Natural killer cell leukemia is a rare form of T-cell leukemia that has a strong association with the Epstein-Barr virus (EBV) and tends to affect younger individuals, with a median age at diagnosis of 40 years. ○ Recurrent chromosome abnormalities include deletions of 6q and 11q. MATURE T-CELL NEOPLASMS Adult T-Cell Leukemia/Lymphoma (ATLL) ○ ATLL is a lymphoid neoplasm that it is known to be associated with early exposure to the human T-cell lymphotropic virus type 1 (HTLV-1) and affects approximately 3% of individuals who carry the virus (median age: 60 years). ○ The most frequent genetic abnormalities include: Rearrangements of the T-cell receptor genes TRG@ at 7p14.1, TRB@ at 7q34, and TRA/D@ at 14q11.2; Gains of the X chromosomes and chromosomes 3 and 7; Rearrangements of 1p, 1q, 2q, 3q, and 17q; and Deletions of 6q, 9p, 13q, and 17p. MATURE T-CELL NEOPLASMS Complex karyogram with several chromosome rearrangements typically seen in adult T-cell leukemia. Gain of chromosomes X, 3, and 7 and deletions 6q and 9p are present in most cases. MATURE T-CELL NEOPLASMS Mycosis Fungoides ○ Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, is characterized by an increased number of CD4+ T-cells in the skin. ○ More advanced cases have an unfavorable prognosis that resembles the clinical behavior seen in patients with Sézary syndrome. ○ Often include rearrangements of the short arm of chromosome 1, particularly of the critical regions 1p32-p36, as well as other numerical and/or structural abnormalities involving chromosomes 3, 6, 10, 11, 12, and 14. MATURE T-CELL NEOPLASMS Sézary Syndrome ○ Sézary syndrome (SS) is a cutaneous T-cell lymphoma similar in many ways to mycosis fungoides except for the presence of erythroderma and lymphadenopathy. ○ This neoplasm occurs in adults over the age of 60 and is associated with an unfavorable prognosis. ○ Rearrangements may involve chromosomes 1, 6, 10, 14, 17, 18, and 19. CYTOGENETICS OF SOLID TUMORS Central Nervous System Tumors Gastrointestinal Tumors Genitourinary Tumors Epithelial Cancers Bone and Soft Tissue Tumors  CENTRAL NERVOUS SYSTEM TUMORS Gliomas ○ Gliomas, the most common primary central nervous system (CNS) tumors, include astrocytomas, oligodendrogliomas, and ependymomas. GLIOMA GENETIC ABERRATION AFFECTED GENE Astrocytomas Grade I (Pilocytic Astrocytoma; PA) Gains of chromosomes 5 and 7 (frequent) BRAF at 7q34 Grade II (Diffuse Astrocytoma) Loss of 10q, 13q, 17p, and 19q IDH1 (2q34) or IDH2 (15q26.1), TP53 and RB1 mutations Grade III (Anaplastic Astrocytoma) Loss of 10q, 13q, 17p, and 19q IDH1 (2q34) or IDH2 (15q26.1) TP53 and RB1 mutations Grade IV (Glioblastoma) Loss of 9p, loss of 10q CDKN2A deletion, PTEN deletion, EGFR amplification, and MDM2 amplification.  CENTRAL NERVOUS SYSTEM TUMORS GLIOMA GENETIC ABERRATION AFFECTED GENE Oligodendroglioma (OD) Unbalanced der(1;19)(q10;p10) with loss of 1p and 19q; 1p/19q codeletion Anaplastic oligodendrogliomas Loss of 9p, in addition to 1p/19q loss CDKN2A/B Ependymomas Losses of 22q and 6q and gains of 1q and 9q NF2,TP53,PTEN, Grade I (myxopapillary ependymoma) MEN2, and Grade II CDKN2A Pilocytic astrocytoma, grade I, from the posterior fossa of a 12-year-old boy: 47,XY,+5,der(14;21)(q10;q10) Oligodendroglioma, grades II–III, from the brainstem of an 8-year-old girl: 57,XX,+der(1;19)(q10;p10)x2,+2,+3, +4,+8,+11,+16,+20, +20,+22. Ependymoma, grade II, from the posterior fossa of a 2-year-old girl: 46,XX,+14,−22 GASTROINTESTINAL TUMORS Liver ○ Hepatoblastoma (HB) is the most common primary malignant tumor of the liver in children. ○ Mesenchymal hamartoma of the liver (HMH) is a rare benign lesion that occurs mainly in infants. GASTROINTESTINAL TUMORS Salivary Gland ○ Pleomorphic adenoma (PA) is a benign mixed salivary gland tumor. ○ Mucoepidermoid carcinoma is the most common primary malignant tumor of the salivary gland. ○ Warthin’s tumor, aka papillary cystadenoma lymphomatosum, is the second most common salivary gland tumor, is a benign neoplasm that arises almost exclusively in the parotid gland. GASTROINTESTINAL TUMORS Dermal ○ Dermatofibrosarcoma protuberans (DFSP) is an intermediate-grade soft tissue malignancy that usually arises in the dermis and subcutaneous tissue of adults. ○ Hidradenoma is a benign sweat gland tumor that often presents as a solitary, slow-growing, solid, or cystic intradermal nodule. GENITOURINARY TUMORS Renal Tumors GENITOURINARY TUMORS Prostate and Bladder Tumors ○ Prostate adenocarcinoma is the most common cancer in males, representing 29% of cancers. GENITOURINARY TUMORS Epithelial Cell Carcinoma GENITOURINARY TUMORS Bone and Soft Tissue Tumors GENITOURINARY TUMORS Bone and Soft Tissue Tumors GENITOURINARY TUMORS Bone and Soft Tissue Tumors