Abstract for presentation at 11th International Congress of Human Genetics

NBS1 gene heterozygous mutations have been assosciated with increase susceptibility to malignancies including breast and ovary cancer, melanoma malignum and medulloblastoma. So far reports on heterozygous NBS1 mutations in lymphoproliferative diseases are rare and controversial. The aim of the present study was to analyse the mutations in all 16 exons of NBS1 gene in children with acute lymphoblastic leukemia (ALL) and to determine the frequency 657del5 mutation carriers of NBS1 gene in population of Wielkopolska region. To discriminate between germinal and somatic mutations DNA was isolated from either leukemic or normal oral epithelium cells. For population study 2090 blood samples from anonymous, unused Guthrie cards have been used. The NBS1 mutations have been detected by PCR-single strand conformation polymorphism and confirmed by direct sequencing. In 113 ALL cases the following four NBS1 gene mutations in 6 patients (frequency 1/19) have been identified: in exon 5 I171V (3 cases), in exon 6 R215W, V210F and 657del5. In addition 23 novel intron variants: IVS14-30A/T, IVS15+88C/G, IVS7-18G/A, and IVS8-42 G/C have been detected. All the above NBS1 mutations have been identified at the time of diagnosis and during remission both in peripheral blood and oral epithelium cells. This indicate that the observed mutations in NBS1 gene are of germinal origin. In the group of 2090 cases 16 heterozygous mutation carriers have been found, giving frequency 1/131. We observed differing regional distribution of heterozygous 657del5 mutation carriers: among 464 samples from the east region of Wielkopolska we found 6 carriers (1/77), opposite to the south region without any carrier among 625 samples analysed. Much higher frequency of NBS1 mutation in ALL cases as compared to population strongly argues that NBS1 is a cancer risk gene.
This work is supported by Ministry of Science and Informatics grants no PBZ-KBN-090/P05/02 and PBZ-KBN-090/P05/2003.