79727

LIN28A

CSDD1|LIN-28|LIN28|ZCCHC1|lin-28A;lin-28 homolog A (C. elegans);LIN28A;lin-28 homolog A (C. elegans)

RNA-binding protein LIN-28|protein lin-28 homolog A|zinc finger CCHC domain-containing protein 1|zinc finger, CCHC domain containing 1

1p36.11

protein-coding

Malignant rhabdoid tumor is a highly aggressive pediatric neoplasm molecularly characterized by inactivating mutations of the SMARCB1 gene, a potent tumor suppressor and member of the SWI/SNF chromatin remodeling complex. It has been suggested that oncogenesis in SMARCB1-deficient cancers, such as malignant rhabdoid tumors, is driven not by the loss of SWI/SNF function but by an aberrant functioning of the BRG1-containing SWI/SNF complex. Since Brg1 is required for self-renewal and pluripotency of mouse embryonic stem cells, we hypothesized that the human malignant rhabdoid tumors may express pluripotency genes such as SALL4, LIN28 , OCT3 and OCT4 (OCT3/4) , NANOG , and TCL1 . To test this hypothesis, we studied the immunohistochemical expression of SALL4, LIN28, OCT3/4, NANOG, and TCL1 in 11 malignant rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumors) and 5 malignant rhabdoid tumors of the kidney. Of the 16 malignant rhabdoid tumors, 14 (88%) tumors showed robust SALL4 and/or LIN28 expression. No tumor showed any significant OCT3/4, NANOG, or TCL1 expression. Our results suggest that malignant rhabdoid tumors may arise from and/or share features with embryonic stem cells or germ cells.

Embryonal tumor with multilayered rosettes (ETMR, previously known as ETANTR) isa highly aggressive embryonal CNS tumor, which almost exclusively affects infants and is associated with a dismal prognosis. Accurate diagnosis is of critical clinical importance because of its poor response to current treatment protocols and its distinct biology. Amplification of the miRNA cluster at 19q13.42 has been identified previously as a genetic hallmark for ETMR, but an immunohistochemistry-based assay for clinical routine diagnostics [such as INI-1for atypical teratoid rhabdoid tumor (AT/RT)] is still lacking. In this study, we screened for an ETMR-specific marker using a gene-expression profiling dataset of more than 1,400 brain tumors and identified LIN28A as a highly specific marker for ETMR. The encoded protein binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis. Using an LIN28A specific antibody, we carried out immunohistochemical analysis of LIN28A in more than 800childhood brain-tumor samples and confirmed its high specificity for ETMR. Strong LIN28A immunoexpression was found in ALL 37 ETMR samples tested, whereas focal reactivity was only present in a small (6/50) proportion of AT/RT samples. ALL other pediatric brain tumors were completely LIN28A-negative. In summary, we established LIN28A immunohistochemistry as a highly sensitive and specific, rapid, inexpensive diagnostic tool for routine pathological verification of ETMR.