Increased cancer risk of heterozygotes with NBS1 germline mutations in poland

Abstract

It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non-Hodgkin lymphoma (2/ 42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations. © 2004 Wiley-Liss, Inc. Key words: NBS1 gene; heterozygous mutation carriers; 657del5 mutation; R215W molecular variant; cancer riskThe chromosomal instability disorder, Nijmegen breakage syndrome (NBS), is characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to X-irradiation and increased predisposition to lymphoid malignancy. 1 The gene mutated in NBS was identified in 1998. [2][3][4] Nibrin, the product of the NBS1 gene, is part of the MRE11/RAD50 complex, which is involved in the repair of DNA double strand breaks (DSBs). Double strand breaks are not only induced by mutagens but are also intermediates of DNA processing in immune gene rearrangements, the maintenance of telomeres, and in meiotic recombination. Nibrin is involved in the processing of all these types of DSBs. 2 This explains the complex NBS phenotype, including the very high incidence of lymphomas and other malignant tumors, which are the major cause of deaths among NBS patients already during childhood and adolescence. 5 The majority of NBS patients are of Central and Eastern European origin and share the common founder mutation in the NBS1 gene, 657del5. 6 NBS shares many clinical and cellular features with ataxiatelangiectasia (AT), and it was shown that they are also pathogenetically related. 7-10 Interestingly, the cancer risk in NBS1 homozygotes is higher than that of AT patients. 5 Heterozygous relatives of AT probands have an approximately 2...

Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia

“…The association of the 657del5 mutation with increased risk of hematological cancer has been recently shown. 3,5 In our study, we observed only one 657del5 mutation in c-ALL patients (1/134) and one in controls (1/195). Similar results were reported by several authors who failed to detect a significant contribution of the 657del5 mutation to lymphoproliferative disease development among both Slavic populations 5 and non-Slavic populations, such as in Germany 5 or Britain.…”

“…Although heterozygous carriers of the NBS1 657del5 mutation have been shown to have an increased risk for breast cancer, melanoma, colon and rectum cancer, 3 other studies have found no association between NBS1 gene mutations and Hodgkin's lymphoma or NHL. [4][5][6] In contrast, Varon et al 7 detected several point mutations in the NBS1 gene among 47 patients with childhood acute lymphoblastic leukemia (ALL).…”

“…Recently, it was shown that heterozygous carriers of germline R215W may have an elevated risk of malignancy, especially of the colon and rectum. 3 The reports on the R215W mutation in lymphoproliferative diseases are controversial. This variant was described in one of 47 German patients with T-ALL, 7 in four of 231 British leukemia cases (two c-ALL, one T-ALL and one AML) and in one of 51 NHL patients.…”

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

“…(21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer,…”

“…(17) Heterozygous mutations in the NBS1 gene have been described in various groups of cancer patients, for example, patients with acute lymphoblastic leukemia (ALL), (18,19) non-Hodgkin's lymphoma (NHL), (20) and in cancer cell lines. (21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer, (24) ovarian cancer, (25) breast cancer (26,27) and NHL. (28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”