Two Brothers with Ataxia-Telangiectasia-like Disorder with Lung Adenocarcinoma

Uchisaka, Naoki; Takahashi, Naomi; Satō, Masaki; Kikuchi, Akira; Mochizuki, Seibu; Imai, Kohsuke; Nonoyama, Shigeaki; Ohara, Osamu; Watanabe, Fumiaki; Mizutani, Shuki; Hanada, Ryoji; Morio, Tomohiro

doi:10.1016/j.jpeds.2009.02.037

Cited by 51 publications

(55 citation statements)

References 8 publications

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“…Presently, the literature describes 18 cases of ATLD and one case of NBSLD that were all linked to mutations in the MRE11 gene and one NBSLD patient with two RAD50 mutations (Hernandez et al 1993;Stewart et al 1999;Pitts et al 2001;Delia et al 2004;Fernet et al 2005;Uchisaka et al 2009;Matsumoto et al 2011;Palmeri et al 2013). The availability of atomic structures of eukaryotic Mre11 and Nbs1 and prokaryotic Rad50 and the high degree of conservation of MRN allow us to map the underlying mutations onto a structural model of the MRN complex (Fig.…”

Section: Mutations In Mre11-rad50-nbs1 In Human Diseasementioning

confidence: 99%

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Schiller

Seifert

Linke-Winnebeck

et al. 2014

Cold Spring Harbor Perspectives in Biology

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DNA double-strand breaks are repaired by two major pathways, homologous recombination or nonhomologous end joining. The commitment to one or the other pathway proceeds via different steps of resection of the DNA ends, which is controlled and executed by a set of DNA double-strand break sensors, endo-and exonucleases, helicases, and DNA damage response factors. The molecular choreography of the underlying protein machinery is beginning to emerge. In this review, we discuss the early steps of genetic recombination and double-strand break sensing with an emphasis on structural and molecular studies.

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Section: Mutations In Mre11-rad50-nbs1 In Human Diseasementioning

confidence: 99%

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Schiller

Seifert

Linke-Winnebeck

et al. 2014

Cold Spring Harbor Perspectives in Biology

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“…Moreover, these people are at risk of severe cancer susceptibility phenotypes. For example, two brothers who were compound heterozygotes for mutations that fell in the amino region of the MRE11A protein died of pulmonary adenocarcinoma before age 20 [9,10], which would seem very unlikely in the absence of an underlying cancer predisposition. Susceptibility to lymphoma is a prominent feature of Nijmegen breakage syndrome, which is caused by biallelic mutation of NBN [11].…”

Section: Introductionmentioning

confidence: 99%

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

et al. 2014

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IntroductionThe MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions?MethodsUsing high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression.ResultsRe-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies >0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR) = 2.88, P = 0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14).ConclusionsThese data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study.

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“…Although immunoglobulin levels are almost normal, the generation of specific functional antibodies is attenuated [24]. It has been thought that ATLD patients do not exhibit predisposition to cancer, but we have identified a Japanese ATLD family who developed lung cancer [25]. An original report described ATLD as a milder phenotype of AT.…”

Section: Ataxia Telangiectasia-like Disorder (Atld)mentioning

confidence: 93%

“…An original report described ATLD as a milder phenotype of AT. However, a more severe phenotype including microcephaly or NBS-like dimorphic features has been reported [25,26]. MRE11A mutation affects M/R/N complex stability, and decreased NBS1 and/or RAD50 is observed.…”

Section: Ataxia Telangiectasia-like Disorder (Atld)mentioning

confidence: 99%

XCIND as a genetic disease of X-irradiation hypersensitivity and cancer susceptibility

Mizutani

Takagi

2012

Int J Hematol

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The XCIND syndrome is named after distinct hypersensitivity to ionizing (X-ray) irradiation, cancer susceptibility, immunodeficiency, neurological abnormality, and double-strand DNA breakage. The disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is one such disease, and is caused by biallelic germline mutation of the Ataxia telangiectasia mutated (ATM) gene. Heterozygous carriers of the ATM mutation, who do not show A-T-like clinical symptoms, are estimated to comprise 1 % of the population. Thus, understanding the biological basis of XCIND, including A-T, should help shed light on the pathogenesis of genetic diseases with cancer susceptibility.

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Two Brothers with Ataxia-Telangiectasia-like Disorder with Lung Adenocarcinoma

Cited by 51 publications

References 8 publications

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

XCIND as a genetic disease of X-irradiation hypersensitivity and cancer susceptibility

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