Submicroscopic deletion of 5q involving tumor suppressor genes (CTNNA1, HSPA9) and copy neutral loss of heterozygosity associated with TET2 and EZH2 mutations in a case of MDS with normal chromosome and FISH results

Molecular Cytogenetics

Fatih Z Boyar²  Karl Chang²  Charles M Strom²  Yongbao Wang³  Dan Jones³  Frederick K Racke²  Mohammed El Naggar²  Arturo Anguiano²  Weina Chen¹  Morteza Hemmat² 

[1] University of Texas southwestern Medical Center, 5323 Harry Hines Blvd, 75235 Dallas, TX, USA;Cytogenetics Department, Quest Diagnostics Nichols Institute, 33608 Ortega Hwy, 92675 San Juan Capistrano, CA, USA;Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, 20151 Chantilly, VA, USA

关键词: HSPA9;    CTNNA1;    ASXL1;    EZH2;    RUNX1;    EZH2;    TET2;    MDS;    Uniparental disomy (UPD);    Copy neutral loss of heterozygosity (cnLOH);   

Others  :  1229058
DOI  :  10.1186/1755-8166-7-35

 received in 2014-03-30, accepted in 2014-05-19,  发布年份 2014

【 摘 要 】

Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q deletion reported to date. The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one involved the entire long arm of chromosome 4; the second involved the distal half of the long arm of chromosome 7, and the third encompassed the entire chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2 (7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were located at segments of cnLOH resulting in their homozygosity. Loss of heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2 are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and additional cnLOH 14q in the follow-up study suggest genetic evolution of the disease and poor prognosis. This study attests to the fact that some patients with a myelodysplastic syndrome who exhibit a normal karyotype may have underlying genetic abnormalities detectable by chromosomal microarray and/or targeted mutation analyses.

【 授权许可】

   
2014 Hemmat et al.; licensee BioMed Central Ltd.

【 图 表 】

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