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A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.

ABSTRACT: We previously identified a functional variant in a let-7 microRNA (miRNA) complementary site in the 3'-untranslated region of the KRAS oncogene (rs61764370) which is associated with cancer. We aimed to investigate the association of this KRAS variant with breast cancer and tumour biology.We assessed frequency distributions of the KRAS variant in 415 patients with histologically confirmed breast cancer and 457 controls from Connecticut, USA (study group 1) and association of this variant with breast-cancer subtypes in 690 Irish women with known oestrogen receptor (ER), progesterone receptor (PR), and HER2 statuses, and 360 controls (study group 2). We pooled data for study groups 1 and 2 with a cohort of 140 women with triple-negative breast cancer and 113 controls to assess the association of the KRAS variant with triple-negative breast cancer risk, and genome-wide mRNA and specific miRNA expression in patients with triple-negative breast cancer.Although frequency distributions of the KRAS variant in study group 1 did not differ between all genotyped individuals, eight (33%) of 24 premenopausal women with ER/PR-negative cancer had the KRAS variant, compared with 27 (13%) of 201 premenopausal controls (p=0.015). In study group 2, the KRAS variant was significantly enriched in women with triple-negative breast cancer (19 [21%] of 90 cases) compared with 64 (13%) of 478 for luminal A, 13 (15%) of 87 for luminal B, and two (6%) of 35 for HER2-positive subgroups (p=0.044). Multivariate analysis in the pooled study groups showed that the KRAS variant was associated with triple-negative breast cancer in premenopausal women (odds ratio 2.307, 95% CI 1.261-4.219, p=0.0067). Gene-expression analysis of triple-negative breast-cancer tumours suggested that KRAS-variant positive tumours have significantly altered gene expression, and are enriched for the luminal progenitor and BRCA1 deficiency signatures. miRNA analysis suggested reduced levels of let-7 miRNA species in KRAS-variant tumours.The KRAS variant might be a genetic marker for development of triple-negative breast cancer in premenopausal women, and altered gene and miRNA expression signatures should enable molecular and biological stratification of patients with this subgroup of breast cancer.US National Institutes of Health.

SUBMITTER: Paranjape T

PROVIDER: S-EPMC3488438 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.

Paranjape Trupti T Heneghan Helen H Lindner Robert R Keane Florence K FK Hoffman Aaron A Hollestelle Antoinette A Dorairaj Jemima J Geyda Kimberly K Pelletier Cory C Nallur Sunitha S Martens John Wm JW Hooning Maartje J MJ Kerin Michael M Zelterman Daniel D Zhu Yong Y Tuck David D Harris Lyndsay L Miller Nicola N Slack Frank F Weidhaas Joanne J

The Lancet. Oncology 20110322 4

<h4>Background</h4>We previously identified a functional variant in a let-7 microRNA (miRNA) complementary site in the 3'-untranslated region of the KRAS oncogene (rs61764370) which is associated with cancer. We aimed to investigate the association of this KRAS variant with breast cancer and tumour biology.<h4>Methods</h4>We assessed frequency distributions of the KRAS variant in 415 patients with histologically confirmed breast cancer and 457 controls from Connecticut, USA (study group 1) and a ...[more]

PMID: 21435948

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Project description:BackgroundSentinel lymph node biopsy is the standard surgical staging approach for operable triple-negative breast cancer (TNBC) with clinically negative axillae. In this study, we sought to develop a model to predict TNBC patients with negative nodal involvement, who would benefit from the exemption of the axillary staging surgery.Materials and methodsWe evaluated 3' untranslated region (3'UTR) profiles using microarray data of TNBC from two Gene Expression Omnibus datasets. Samples from GSE31519 were divided into training set (n = 164) and validation set (n = 163), and GSE76275 was used to construct testing set (n = 164). We built a six-member 3'UTR panel (ADD2, COL1A1, APOL2, IL21R, PKP2, and EIF4G3) using an elastic net model to estimate the risk of lymph node metastasis (LNM). Receiver operating characteristic and logistic analyses were used to assess the association between the panel and LNM status.ResultsThe six-member 3'UTR-panel showed a high distinguishing power with an area under the curve of 0.712, 0.729, and 0.708 in the training, validation, and testing sets, respectively. After adjustment by tumor size, the 3'UTR panel retained significant predictive power in the training, validation, and testing sets (odds ratio = 4.93, 4.58, and 3.59, respectively; p < .05 for all). A combinatorial analysis of the 3'UTR panel and tumor size yielded an accuracy of 97.2%, 100%, and 100% in training, validation, and testing set, respectively.ConclusionThis study established an integrative 3'UTR-based model as a promising predictor for nodal negativity in operable TNBC. Although a prospective study is needed to validate the model, our results may permit a no axillary surgery option for selected patients.Implications for practiceCurrently, sentinel lymph node biopsy is the standard approach for surgical staging in breast cancer patients with negative axillae. Prediction estimation for lymph node metastasis of breast cancer relies on clinicopathological characteristics, which is unreliable, especially in triple-negative breast cancer (TNBC)-a highly heterogeneous disease. The authors developed and validated an effective prediction model for the lymph node status of patients with TNBC, which integrates 3'UTR markers and tumor size. This is the first 3'UTR-based model that will help identify TNBC patients with low risk of nodal involvement who are most likely to benefit from exemption axillary surgery.

Project description:Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.

Dataset Information

A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.

Publications

A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.

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