Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome

S Brandon S. Twardy, Deborah Schloff, Anwar N. Mohamed Affiliation

Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine and Detroit Medical Center, Detroit MI, USA

Previous history

Preleukaemia

Malignant disease

Inborn condition

Main items

Note

A non-contributory past medical history. Patient had no previous leukemia or malignancy, and had not received chemotherapy or radiation in the past.

Clinics case report

Age

52 yrs

Sex

Liver

Spleen

-t

Lymph nodes

Cns involv

Blood data

Wbc

1.7

11.3

Platelets

Blasts

Peripheral blood smear showed pancytopenia with 1% circulating myeloblasts.

Bone marrow

Bone marrow biopsy was hypercellular (90%) with dysmegakaryopoiesis, dysgranulopiesis, markedly increased erythrogenesis with dysplastic features, and 10% myeloblasts with no Auer rods. No metastatic tumor or granuloma

Cyto path

Phenotype

Findings were consistent with myelodysplastic syndrome, best classified as refractory anemia with excess blasts (RAEB-2)

Immunophenotype

Flow cytometric analysis of the bone marrow aspirate detected 5% myeloblasts with dim expression of CD45. Blasts were positive for CD13, CD33, CD34, CD117, CD38, and HLA-DR. Erythroid precursors constituted 55% of the gated cells and were positive for CD36 and glycophorin A.

Rearranged ig tcr

Electron microscopy

Not performed

Precise diagnosis

Myelodysplastic syndrome, RAEB-2

Survival data

Date diagnosis

01-2015

Treatment

In January 2015, the patient received high dose Ara-C chemotherapy followed by multiple doses of Vidaza. In December 2015, he underwent allogeneic peripheral blood stem cell transplant from a matched-unrelated female donor.

Complete remission

Treatment relat death

Status

D 80 days after transplant

Survival

Karyotype

Sample

Bone marrow aspirate

Culture time

24 hours unstimulated culture; 48 hours with 10% conditioned media

Banding

G- banding

Results

clone 2 46,XY,del(5)(q13q33),add(20)(q11.2)[3]

Mol cytogenet results

Fluorescence in situ hybridization (FISH) was performed on the pellet from the harvested bone marrow specimen using the MDS panel DNA probes that included D5S23:D5S721/5p15.2, EGR1/5q31, D7Z1/CEP-7, D7S486/7q31, D8Z2/CEP-8, and D20S108/20q12. Results of FISH revealed an amplification the D7S486 /7q31 region in approximately 60% of cells (>6 copies per nucleus), and deletions of EGR1/5q and 20q12 in 10% of cells. In addition, we investigated the status of MET as a candidate oncogene for the amplified 7q31 region. Accordingly, the LSI MET SpectrumRed probe along with CEP-7 SpectrumGreen as a control were hybridized on the same specimen. The LSI MET probe is approximately 456 kb and contains the entire MET gene on chromosome 7q31.2. The hybridization revealed amplification of the MET gene with only 2 signals/copies for the control CEP-7 (Figure 2). All FISH probes were purchased from Abbott Molecular, Downers Grove IL, USA.

Images

Figure 1: G-banded karyotype at time of diagnosis showing multiple abnormalities including a ring chromosome, and other unbalanced aberrations

Figure 2: FISH with LSI MET SepectrumRed probe showing multiple red signals for MET while two green signals for centromere 7, On metaphase cells the red signals hybridized to the ring chromosome.

Comments section

Comments

Despite aggressive therapy, our patient never achieved remission, and he died from disease progression shortly after transplant. The complex karyotype as well as MET amplification certainly contributes to the dismal sequence of the disease. Therapeutic agents targeting the MET pathway may help improve patient survival.

Bibliography

Pubmed ID	Last Year	Title	Authors
17064770	2007	HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms.	Cigognini D et al
24439223	2014	Chromosome 7q31.1 deletion in myeloid neoplasms.	Tripputi P et al
9716011	1998	Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines.	Pons E et al
22683780	2012	Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia.	Kentsis A et al
25212607	2014	A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target.	Ferrucci A et al
23804425	2013	Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma.	Moschetta M et al
24326130	2013	Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines.	Phillip CJ et al
18379349	2008	MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort.	Beau-Faller M et al
25887320	2015	The clinical and functional significance of c-Met in breast cancer: a review.	Ho-Yen CM et al
25055117	2014	Targeting MET Amplification as a New Oncogenic Driver.	Kawakami H et al

Citation

S Brandon S. Twardy, Deborah Schloff, Anwar N. Mohamed

Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome

Atlas Genet Cytogenet Oncol Haematol. 2016-06-01

Online version: http://atlasgeneticsoncology.org/case-report/208884/amplification-of-the-met-7q31-gene-in-a-patient-with-myelodysplastic-syndrome