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

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

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
M
Liver
-
Spleen
-t
Lymph nodes
-
Cns involv
-

Blood data

Wbc
1.7
Hb
11.3
Platelets
50
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
t
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
15

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

Atlas Image
Figure 1: G-banded karyotype at time of diagnosis showing multiple abnormalities including a ring chromosome, and other unbalanced aberrations
Atlas Image
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 IDLast YearTitleAuthors
170647702007HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms.Cigognini D et al
244392232014Chromosome 7q31.1 deletion in myeloid neoplasms.Tripputi P et al
97160111998Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines.Pons E et al
226837802012Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia.Kentsis A et al
252126072014A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target.Ferrucci A et al
238044252013Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma.Moschetta M et al
243261302013Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines.Phillip CJ et al
183793492008MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort.Beau-Faller M et al
258873202015The clinical and functional significance of c-Met in breast cancer: a review.Ho-Yen CM et al
250551172014Targeting 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