1. Myeloid tumor panel

Myeloid tumor panel

September 28, 2018

Disease summary:

Myeloid malignancies are clonal diseases of hematopoietic progenitor cells (cells that are capable of multiplying and producing additional blood cells of a particular lineage) resulting from genetic and epigenetic alterations that disrupt proliferation, differentiation and self-renewal of hematopoietic cells. Myeloid tumors represent the fourth most frequently diagnosed cancer in developed countries 1, and they include acute (acute myeloid leukemia, AML) and chronic forms (myelodysplastic syndrome, chronic myelogenous leukemia, juvenile myelomonocytic leukemia and others).

Most myeloid tumors contain high numbers of somatic mutations 2, 3, 4 - genetic changes that are not inherited but created within the tumor itself. These mutations significantly contribute to the pathogenesis, progression and prognosis of myeloid malignancies. Specific somatic mutations are known to be associated with response or resistance to specific cancer therapies, in some cases they can help determine prognosis for patients with myeloid tumors and select the best therapeutic strategy for each patient. 


Somatic, not-inherited

8.6/100,000 5 (3.7/100,000 for AML; 1.8/100,000 for myelodysplastic syndrome) 5

Clinical symptoms: 1, 4

  • Weight loss
  • Fatigue and weakness
  • Night sweats
  • Fever, with or without infections
  • Loss of appetite
  • Excessive bruising and bleeding
  • Enlarged spleen

Diagnostic criteria: 6

  • Cytopenia that cannot be explained by other etiology
  • Dysplastic features in at least 10% of major blood cell lines
  • Identification of >5-19% of myeloblasts in bone marrow smear or >2%-19% of circulating myeloblasts 
  • Myeloid dysplastic syndrome associated chromosomal abnormality
  • Flow cytometry abnormalities of bone marrow or peripheral blood cells
  • Identification of somatic mutations in one of the associated genes (Table 1)
  • Imatinib mesylate: a small molecule tyrosine kinase inhibitor, approved for use in Philadelphia chromosome–positive chronic myelogenous leukemia, indicated for chronic myelogenous leukemia
  • Interferon alfa: produces hematologic and molecular remissions in some patients with chronic myelogenous leukemia
  • Hydroxyurea: For patients with chronic myelogenous leukemia who are intolerant to interferon-alfa therapy
  • Dasatinib: Indicated for the treatment of adult patients with chronic myeloid leukemia who are resistant/intolerant to imatinib
  • Nilotinib: Indicated for the treatment of chronic-phase and accelerated-phase Philadelphia chromosome-positive chronic myelogenous leukemia in adult patients who are resistant or intolerant to prior therapy including imatinib.
  • Lenalidomide, azacitidine, and decitabine, FDA-approved drugs that can slow the progression of chronic myeloid disease
  • Allogenic or autologous transplantation of bone marrow or peripheral blood cells
  • Essential thrombocytosis
  • Hypereosinophilic syndrome
  • Non-Hodgkin lymphoma
  • Primary myelofibrosis
  • Secondary thrombocytosis
  • Systemic mastocytosis
  • Waldenstrom macroglobulinemia

Myeloid Tumor Panel NGS Panel which includes somatic mutation analysis at a mean coverage depth of >1,000x of the genes listed in Table 1

  • Individuals with a myeloid tumor: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML).
  • Patients without clinical diagnosis but with classical clinical symptoms and possible changes in blood cell morphology and count.
  • Individuals with early-stage disease where a mutational profile from multiple genes could inform diagnosis or disease stratification, prognosis, and treatment options.
  • For late-stage cancers, the test is designed to evaluate options for alternative treatments, including targeted therapies

Confirmation of a clinical diagnosis of myeloid tumor through genetic testing can allow for enhanced understanding of the disease cause and prognosis and may direct medical management, such as treatment selection and monitoring.


Table1: Myeloid Tumor Panel

GeneOMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD exclusive variant numbers (++)
ASXL1 612990 Bohring-Opitz syndrome; Myelodysplastic syndrome, somatic

AD7
CEBPA 116897 Leukemia, acute myeloid; Leukemia, acute myeloid, somatic AD4
DNMT3A 602769 Acute myeloid leukemia, somatic; Tatton-Brown-Rahman syndrome AD1
ETV6 600618 Leukemia, acute myeloid, somatic; Thrombocytopenia 5 AD1
EZH2 601573 Weaver syndrome AD3
IDH1 147700 {Glioma, susceptibility to, somatic} --
IDH2 147650 D-2-hydroxyglutaric aciduria 2 -1
KIT 164920 Mast cell disease; Piebaldism; Germ cell tumors, somatic; Leukemia, acute myeloid; Gastrointestinal stromal tumor, familial AD, Isolated cases14
KRAS 190070 Arteriovenous malformation of the brain, somatic; Bladder cancer, somatic; Breast cancer, somatic; Gastric cancer, somatic; Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic; Lung cancer, somatic; Pancreatic carcinoma, somatic; Leukemia, acute myeloid; Noonan syndrome 3; RAS-associated autoimmune leukoproliferative disorder; Cardiofaciocutaneous syndrome 2 AD8
NPM1 164040 Leukemia, acute myeloid, somatic -2
NRAS 164790 Colorectal cancer, somatic; Melanocytic nevus syndrome, congenital, somatic; Epidermal nevus, somatic; Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic; Thyroid carcinoma, follicular, somatic; Neurocutaneous melanosis, somatic; Noonan syndrome 6; ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic AD4
PTPN11 176876 LEOPARD syndrome 1; Metachondromatosis; Noonan syndrome 1; Leukemia, juvenile myelomonocytic, somatic AD11
RAD21 606462 Cornelia de Lange syndrome 4 AD12
RUNX1 151385 Platelet disorder, familial, with associated myeloid malignancy; Leukemia, acute myeloid AD8
SF3B1 605590 Myelodysplastic syndrome, somatic --
SMC1A 300040 Cornelia de Lange syndrome 2 XL D9
SMC3 606062 Cornelia de Lange syndrome 3 AD26
STAG2 300826 - --
TET2 612839 Myelodysplastic syndrome, somatic -2
TP53 191170 Breast cancer; Colorectal cancer; Hepatocellular carcinoma; {Glioma susceptibility 1}; Li-Fraumeni syndrome; Adrenal cortical carcinoma; Osteosarcoma; Pancreatic cancer; Choroid plexus papilloma; Nasopharyngeal carcinoma; {Basal cell carcinoma 7} AD, AR, MF, Somatic mutation12
U2AF1 191317 - --
WT1 607102 Frasier syndrome; Mesothelioma, somatic; Wilms tumor, type 1; Denys-Drash syndrome; Nephrotic syndrome, type 4; Meacham syndrome AD, Somatic mutation11

Abbreviations:

AD autosomal dominant; AR autosomal recessive; XLD X-linked; MF multifactorial; MC mitochondrial