- PgmNr 2430/W: ADAM32 amplification in pediatric malignancies.
V.T. Tonk 1; A.R. Rajan 2; S.S. Singh 2; K.B. Bhende 1; S.T. Tonk 2; S.A. Awasthi 2
1) Pediatrics, TTUHSC, Lubbock, Texas.; 2) Internal Medicine, TTUHSC, Lubbock, Texas.
DNA microarray techniques allow the simultaneous detection of vast number of copy number alterations (CNA) in cancers, including previously unknown ones. The study presented here was aimed at surveying the genes and types of CNA found in the pediatric cancer patient population in the west texas region and was done at TTUHSC, Lubbock. Towards this goal, we performed a retrospective analysis of data obtained from Cytosure Constitutional v3 Microarray that is used for studies of developmental disorders. 198 cases over the previous 5 years were selected for study. The majority of cases were of pediatric malignancies, though some adult cancers and benign hematological diseases were included. We found that the most frequent CNAs were at the following loci: 14q11.2 (127 cases), 8p11.21-8p11.22 (98 cases), 15q11.1-15q11.2 (82 cases), 14q32.33, 9p24 and 9p13. The most affected locus being 14q11.2 was expected as ALL was strongly represented. The 8p11.21-8p11.22 locus was of interest because in this pediatric population, we found that gains outnumbered losses by 4.8-fold (81 vs 17 cases) at this locus, greater than for any other locus. LOH of 8p is reported to be frequent in human breast cancer and also found in other endodermal origin adult solid tumors, but not previously reported for pediatric patients (PMID: 29682206). Genes at this locus previously shown to be involved with gains or amplifications include DUSP26 (gain 14%, loss 34%), ZNF703 (gain 26%, loss 20%) (REF). In this (primarily pediatric) population, CNAs were most frequent at ADAM32 and found in all types of cancer: T-cell Lymphoma, ALL, Enchondroma, AML, Wilm’s Tumor, Hepatocellular Carcinoma, Breast Cancer, Neuroblastoma, Rhabdomyosarcoma, Fibromatosis, Chondroblastoma and Giant Cell Tumor of the Bone. Other affected genes at this locus were KAT6A, TACC1, GPAT4 and TM2D2. Chromosomal translocations with breakpoints at these loci have been reported in breast and other cancers. To investigate whether these genes could be involved in promotion of cancer growth, we conducted studies to determine whether siRNA knockdown would affect growth of adult cancer cell lines. Interestingly, we found relatively small and inconsistent effects of ADAM32 knockdown. In contrast, knockdown of TACC1 kills inhibited cancer growth by 34-68%. Consistent with its function in the mitotic spindle, TACC1 knockdown resulted in abnormal metaphases. Out studies suggest TACC1 is a potential therapeutic target.