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

Mosor, Maria; Ziółkowska, Iwona; Pernak-Schwarz, Monika; Januszkiewicz‐Lewandowska, Danuta; Nowak, Jerzy

doi:10.1038/sj.leu.2404285

Cited by 40 publications

(38 citation statements)

References 8 publications

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“…A set of 20 specific intronic primers flanking each exon of the NBS1 gene was designed as described earlier. (19) The amplification reactions were carried out in a total reaction volume of 25 μL, containing 1 U Taq DNA Polymerase, 1× PCR buffer with 15 mM MgCl 2 (Eppendorf, Germany), 0.4 M of each dNTP (Sigma-Aldrich, Germany), 10 pmol of primers (Oligo, Poland) and 50-100 ng genomic DNA. All samples were analyzed by PCR-single-strand conformation polymorphism (SSCP).…”

Section: Methodsmentioning

confidence: 99%

“…The substitution A > G at 511 (p.I171V) was investigated by PCR-restriction fragment length polymorphism (RFLP) analysis of the mutation with restriction enzymes, as described earlier. (19) Samples that showed an aberrant shift in either PCR-SSCP or PCR-RFLP were purified with a QIAquick PCR Purification Kit (Qiagen, Germany) and sequenced directly on an ABI PRISM310 Sequencer with the use of a BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, USA).…”

Section: Methodsmentioning

confidence: 99%

“…(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.…”

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confidence: 99%

“…(14) Recent findings show that besides spontaneous chromosome instability, (15,16) cells from NBS1 gene mutation carriers are characterized by a distinct gene expression phenotype. (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.…”

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

Ziółkowska

Mosor

Wierzbicka³

et al. 2007

Cancer Science

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The high incidence of multiple primary tumors (MPT) is a significant problem in head and neck tumor treatment. Recent studies suggest that carriers of heterozygous mutations in the NBS1 gene have an increased risk of malignant tumor development. The aim of our research was to assess the frequency of NBS1 mutations in patients with larynx cancer only (LC) and with MPT. The MPT group consisted of patients with one cancer localized to the larynx (primary or second) and another at another site. DNA from 175 patients with LC and 93 patients with MPT was analyzed using the single-strand conformation polymorphism method and direct sequencing. We found nine carriers of the I171V mutation among these 268 cancer patients and only one carrier among 500 population controls (0.2%). Four carriers of the I171V mutation were detected among 175 LC patients (2.3%) and five among 93 patients with MPT (5.4%). The frequencies of the I171V mutation carriers in LC and MPT patients were significantly higher than in controls (odds ratio D espite recent advances in the diagnosis and treatment of head and neck squamous cell carcinoma (HNSCC), the survival rate of patients with these tumors is not improving. One of the reasons for this is the frequent development of second primary tumors (SPT). Among HNSCC patients, the frequency of SPT occurrence ranges from 12 to 30% with a constant rate of 2-3% per year for patients who survive for more than 10 years.[(1-3) The first tumor is responsible for 15% of patient deaths, whereas the second tumor is the cause of death in 71% of cases. Squamous cell carcinoma is the predominant histological type of the second tumor. (4) In the etiology of multiple primary tumors (MPT) of the head and neck, tobacco and alcohol abuse ('condemned mucosa theory') are essential but are not the only causal factors.(5) It is supposed that genetic factors play a great role in the occurrence of the first tumor and, in addition, predispose the patient to the development of a second primary tumor. Because of reduced DNA repair capacity in patients who had two or more independent malignancies, (6) it has been suggested that alterations in DNA repair genes may play a significant role in head and neck tumor development.The NBS1 gene belongs to a group of double-strand break repair genes and is located on chromosome band 8q21.3. (7)(8)(9) Biallelic mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS, OMIM 251260), classified to a group of chromosomal instability syndromes. NBS is a rare autosomal recessive disorder, occurring mainly in central and eastern Europe.(10) The most common is the homozygous 657del5 mutation, observed in 90% of NBS patients. The protein product of the NBS1 gene, nibrin (p95, NBS1), is a member of the MRE11-RAD50-nibrin complex, (7) which is involved in DNA double-strand break repair by homologous recombination or non-homologous end joining, meiotic recombination and the DNA damage response. (7,11) The MRE11-RAD50-nibrin complex is also required for activation of the damage c...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

Ziółkowska

Mosor

Wierzbicka³

et al. 2007

Cancer Science

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“…Homozygous mutations in the NBN gene, resulting in the production of an abnormally short version of the nibrin protein, lead to Nijmegen breakage syndrome (NBS) and increased susceptibility to tumorigenesis (5)(6)(7). Heterozygous variants in this gene, including p.I171V (c.551A>G), c.657delACAAA and p.R215W (c.643C>T), have been described as risk factors for several malignancies, including leukemia, melanoma, breast, ovarian, prostate, larynx and colorectal cancer (8)(9)(10)(11)(12). To the best of our knowledge, there is no report regarding the association of the aforementioned mutations with lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

et al. 2015

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Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

Smith

Lavoie

Walsh

et al. 2019

Genes Chromosomes & Cancer

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High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD‐ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer‐relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11‐encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10−3), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS‐independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD‐ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

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

Abstract: mutation in any of 22 JMML patients in our series. 4 We conclude that the JAK2 V617F in pediatric MPD and leukemia patients is less frequent than that in adults, and that JAK2 mutation is rarely involved in the pathogenesis of pediatric hematologic malignancies.

Cited by 40 publications

References 8 publications

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

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

Heterozygous p.I171V mutation of the NBN gene as a risk factor for lung cancer development

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

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