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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

ABSTRACT: PURPOSE:CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION:Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

SUBMITTER: Muranen TA

PROVIDER: S-EPMC5382131 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Muranen Taru A TA Greco Dario D Blomqvist Carl C Aittomäki Kristiina K Khan Sofia S Hogervorst Frans F Verhoef Senno S Pharoah Paul D P PDP Dunning Alison M AM Shah Mitul M Luben Robert R Bojesen Stig E SE Nordestgaard Børge G BG Schoemaker Minouk M Swerdlow Anthony A García-Closas Montserrat M Figueroa Jonine J Dörk Thilo T Bogdanova Natalia V NV Hall Per P Li Jingmei J Khusnutdinova Elza E Bermisheva Marina M Kristensen Vessela V Borresen-Dale Anne-Lise AL Peto Julian J Dos Santos Silva Isabel I Couch Fergus J FJ Olson Janet E JE Hillemans Peter P Park-Simon Tjoung-Won TW Brauch Hiltrud H Hamann Ute U Burwinkel Barbara B Marme Frederik F Meindl Alfons A Schmutzler Rita K RK Cox Angela A Cross Simon S SS Sawyer Elinor J EJ Tomlinson Ian I Lambrechts Diether D Moisse Matthieu M Lindblom Annika A Margolin Sara S Hollestelle Antoinette A Martens John W M JWM Fasching Peter A PA Beckmann Matthias W MW Andrulis Irene L IL Knight Julia A JA Anton-Culver Hoda H Ziogas Argyrios A Giles Graham G GG Milne Roger L RL Brenner Hermann H Arndt Volker V Mannermaa Arto A Kosma Veli-Matti VM Chang-Claude Jenny J Rudolph Anja A Devilee Peter P Seynaeve Caroline C Hopper John L JL Southey Melissa C MC John Esther M EM Whittemore Alice S AS Bolla Manjeet K MK Wang Qin Q Michailidou Kyriaki K Dennis Joe J Easton Douglas F DF Schmidt Marjanka K MK Nevanlinna Heli H

Genetics in medicine : official journal of the American College of Medical Genetics 20161006 5

<h4>Purpose</h4>CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).<h4>Methods</h4>Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,0 ...[more]

PMID: 27711073

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Project description:PurposeCHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and methodsCHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

Project description:INTRODUCTION: Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. METHODS: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. RESULTS: We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. CONCLUSIONS: We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.

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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

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