Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours

Nowak, Jerzy; Mosor, Maria; Ziółkowska, Iwona; Wierzbicka, Małgorzata; Pernak-Schwarz, Monika; Przyborska, Marta; Rożnowski, Krzysztof; Pławski, Andrzej; Słomski, Ryszard; Januszkiewicz, Danuta

doi:10.1016/j.ejca.2008.01.006

Cited by 38 publications

(25 citation statements)

References 15 publications

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“…The occurrence of the p.I171V variant in the NBN gene has been previously linked with elevated risk of several types of cancer. A significantly higher frequency of the p.I171V variant was observed in ALL, breast, larynx and colorectal cancer, and in multiple primary tumors of the head and neck (9,13,15). However, such an association was not observed for solid malignancies in children (11).…”

Section: Discussionmentioning

confidence: 84%

“…DNA was extracted from blood using the columns provided in the QIAamp DNA Blood Mini Kit (Qiagen GmbH, Hilden, Germany), according to the manufacturer's instructions, and from Guthrie cards, as described previously (13,15). The mutation in the fifth exon of the NBN gene (p.I171V) was assessed by restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) products, using MunI (MfeI) restriction enzyme (Fermentas, Thermo Fisher Scientific, Inc., Pittsburgh, PA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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Section: Discussionmentioning

confidence: 84%

Section: Methodsmentioning

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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“…Mutations in the NBS1 gene have been associated with increased risk of breast cancer (14)(15)(16). Persistent radiation induced NBS1 foci has been associated with chromosomal instability and increased breast cancer risk (13).…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the Nijmegen breakage syndrome 1 gene increases mammary tumor latency and metastasis

Wan

Crowe

2012

Int J Oncol

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Abstract. Human diseases such as Nijmegen breakage syndrome due to mutations in the NBS1 gene result in defects in resection of double strand breaks. NBS1 functions as part of the MRN complex which functions in homologous recombination and non-homologous end joining. NBS is a rare human autosomal recessive disorder caused by hypomorphic mutations. At the cellular level, NBS is characterized by radiosensitivity, chromosomal breakage and defective cell cycle checkpoints. NBS1 null mutations result in early embryonic lethality in mice, but NBS1 hypomorphic mutants are viable. Cells from these mice are defective in S phase and G2/M checkpoints. In humans, NBS1 polymorphisms have been associated with increased risk of breast cancer. MRN expression was reduced in the majority of breast tumors, and low expression of MRN correlated with increased histologic grade and estrogen receptor negativity. While these studies have shown NBS1 to be important in clinical outcomes of patients with breast cancer, mammary tumors are rare in the NBS1 haploinsufficient mouse. To better understand the role of NBS1 in mammary tumorigenesis, we examined the NBS1+/-;MMTV-neu mouse model. Mammary tumor latency was markedly increased in NBS1+/-;neu mice compared to NBS1+/+;neu control animals. This effect was due to increased apoptosis in early NBS1+/-;neu mammary tumors. However, NBS1+/-;neu mammary tumors were highly metastatic and demonstrated clear differences in gene expression profiles compared to control tumors. We concluded that NBS1 haploinsufficiency results in increased mammary tumor latency and metastasis.

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“…To date, the NBS1-I171V polymorphic variant was detected frequently only in Polish patients with breast cancer, head and neck cancer, and colorectal cancer (25)(26)(27)(28). However, other groups did not find a similar association in European patients with breast cancer, leukemia, or lymphoma (29)(30)(31).…”

Section: Nbs1-i171v Polymorphic Variant Increases the Risk Of Breast mentioning

confidence: 99%

A Rare Polymorphic Variant of NBS1 Reduces DNA Repair Activity and Elevates Chromosomal Instability

Yamamoto¹,

Miyamoto²,

Tatsuda

et al. 2014

Cancer Research

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Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia. This polymorphic variant is located in the N-terminal region that interacts with other DNA repair factors. In earlier work, we had identified a remarkable number of structural chromosomal aberrations in a patient with pediatric aplastic anemia with a homozygous polymorphic variant of NBS1-I171V; however, it was unclear whether this variant affected DSB repair activity or chromosomal instability. In this report, we demonstrate that NBS1-I171V reduces DSB repair activity through a loss of association with the DNA repair factor MDC1. Furthermore, we found that heterozygosity in this polymorphic variant was associated with breast cancer risk. Finally, we showed that this variant exerted a dominant-negative effect on wild-type NBS1, attenuating DSB repair efficiency and elevating chromosomal instability. Our findings offer evidence that the failure of DNA repair leading to chromosomal instability has a causal impact on the risk of breast cancer development. Cancer Res; 74(14); 3707-15. Ó2014 AACR.

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Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours

Cited by 38 publications

References 15 publications

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

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

Haploinsufficiency of the Nijmegen breakage syndrome 1 gene increases mammary tumor latency and metastasis

A Rare Polymorphic Variant of NBS1 Reduces DNA Repair Activity and Elevates Chromosomal Instability

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