Dataset Information

CAG repeat size in Huntingtin alleles is associated with cancer prognosis.

ABSTRACT: The abnormal expansion of a ?36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (?27) than in those with a CAG tract <27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).

SUBMITTER: Thion MS

PROVIDER: S-EPMC4989202 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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CAG repeat size in Huntingtin alleles is associated with cancer prognosis.

Thion Morgane Sonia MS Tézenas du Montcel Sophie S Golmard Jean-Louis JL Vacher Sophie S Barjhoux Laure L Sornin Valérie V Cazeneuve Cécile C Bièche Ivan I Sinilnikova Olga O Stoppa-Lyonnet Dominique D Durr Alexandra A Humbert Sandrine S

European journal of human genetics : EJHG 20160316 9

The abnormal expansion of a ≥36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that pr ...[more]

PMID: 26980106

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Project description:BackgroundThe length of the huntingtin (HTT) CAG repeat is strongly correlated with both age at onset of Huntington's disease (HD) symptoms and age at death of HD patients. Dichotomous analysis comparing HD to controls is widely used to study the effects of HTT CAG repeat expansion. However, a potentially more powerful approach is a continuous analysis strategy that takes advantage of all of the different CAG lengths, to capture effects that are expected to be critical to HD pathogenesis.Methodology/principal findingsWe used continuous and dichotomous approaches to analyze microarray gene expression data from 107 human control and HD lymphoblastoid cell lines. Of all probes found to be significant in a continuous analysis by CAG length, only 21.4% were so identified by a dichotomous comparison of HD versus controls. Moreover, of probes significant by dichotomous analysis, only 33.2% were also significant in the continuous analysis. Simulations revealed that the dichotomous approach would require substantially more than 107 samples to either detect 80% of the CAG-length correlated changes revealed by continuous analysis or to reduce the rate of significant differences that are not CAG length-correlated to 20% (n = 133 or n = 206, respectively). Given the superior power of the continuous approach, we calculated the correlation structure between HTT CAG repeat lengths and gene expression levels and created a freely available searchable website, "HD CAGnome," that allows users to examine continuous relationships between HTT CAG and expression levels of ∼20,000 human genes.Conclusions/significanceOur results reveal limitations of dichotomous approaches compared to the power of continuous analysis to study a disease where human genotype-phenotype relationships strongly support a role for a continuum of CAG length-dependent changes. The compendium of HTT CAG length-gene expression level relationships found at the HD CAGnome now provides convenient routes for discovery of candidates influenced by the HD mutation.

Dataset Information

CAG repeat size in Huntingtin alleles is associated with cancer prognosis.

Publications

CAG repeat size in Huntingtin alleles is associated with cancer prognosis.

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