Mutations in the N-terminal domain of DFF45 in a primary germ cell tumor and in neuroblastoma tumors.
Artikel i vetenskaplig tidskrift, 2004

DFF45 has essential functions in the final stage of apoptosis by acting both as a folding chaperone and a DNase inhibitor of DFF40. The gene encoding DFF45 (DFFA) maps to the consensus deleted region in primary neuroblastoma (NB; 1p36.2-3) and within the homozygously deleted region in an NB cell line (1p36.2). DFF45 is therefore an attractive candidate NB tumor suppressor. In a previous study we found a rare allele variant, causing a non-polar to a polar amino acid exchange (Ile69Thr) in a preserved hydrophobic patch of DFF45, and we also found DFFA to be preferentially expressed in favorable NB tumors. We have extended the previous study and performed mutation analyses in another 56 NB tumors (100 in total) as well as a set of other tumors for coding mutations in DFFA. We have also performed studies of the DFFA expression in tumors using real-time PCR. We found a missense mutation (Ile15Met) in the remaining allele of a teratoma with heterozygous deletion of 1p, and a three base-pair deletion in an NB of unknown stage causing a deletion of amino acid 37 in DFF45. The one-base substitution detected in the teratoma was not present in the patients constitutional DNA, i.e. it is a true mutation present in the tumor DNA only. In conclusion, three different coding alterations have been found in the region encoding the N-terminal regulatory domain of DFF45, responsible for binding and achieving its chaperone and inhibitor functions on other proteins. Moreover, by real-time RT-PCR expression study, we found the mRNA level of DFFA to be significantly (p=0.038) reduced by a factor of 1.7 times in NB tumors of unfavorable outcome.

Humans

Deoxyribonucleases

DNA Mutational Analysis

Missense

Apoptosis Regulatory Proteins

Neoplasm Staging

Intracellular Signaling Peptides and Proteins

Reverse Transcriptase Polymerase Chain Reaction

Apoptosis

genetics

Neoplasms

Prognosis

RNA

genetics

Messenger

Mutation

genetics

Germ Cell and Embryonal

analysis

Neuroblastoma

Författare

Frida Abel

Göteborgs universitet

Rose-Marie Sjöberg

Göteborgs universitet

Cecilia Krona

Göteborgs universitet

Staffan Nilsson

Chalmers, Institutionen för matematisk statistik

Göteborgs universitet

Tommy Martinsson

Göteborgs universitet

International Journal of Oncology

1019-6439 (ISSN)

Vol. 25 1297-302

Ämneskategorier

MEDICIN OCH HÄLSOVETENSKAP

PubMed

15492818