Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

Pande, Mala; Bondy, Melissa L.; Anh, Kim; Şahin, Ayşegül; Jin, Ying; Mills, Gordon B.; Thompson, Patricia A.; Brewster, Abenaa M.

doi:10.1007/s10549-014-3081-9

Cited by 23 publications

(19 citation statements)

References 33 publications

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“…However, an increased risk of BC was not found in two other studies [89,92]. Recently, Pande et al found an association between the IGF-I SNP rs1520220 and poor DFS in women with stage I-II BC [71].…”

Section: Igf-i Snpsmentioning

confidence: 92%

“…In a study relating these associations with the clinical evolution, a shorter DFS was related to higher frequency of LEP (22548) A allele, and OS was reduced in patients carrying the LEPR Gln223Arg allele [67]. In contrast, LEPR single nucleotide polymorphism (SNP) rs11585329 (622G.T) has recently been associated with improved DFS in women with stage I-II BC [71].…”

Section: Leptin and Leptin Receptor Single Nucleotide Polymorphismsmentioning

confidence: 99%

“…The SNP rs2677760 in PIK3CA is associated with reduced DFS in women with stage I-II BC [71]. Moreover, a recent metaanalysis showed that PIK3CA gene mutations correlate with ER/progesterone receptor (PR) expression (p , .00001) and relapse-free survival (p 5 .03), but not OS in unsorted BC patients [92].…”

Section: Pik3ca Snpsmentioning

confidence: 99%

“…BC development in obese women is also related to a genetic susceptibility, that is specific to each ethnicity, as revealed by the analysis of several gene SNPs (Table 1). In whites, major polymorphisms associated with the BC risk in obese women include LEP-2548 AA [66], PON1 Leu55Met [68],TNF-a-308G.A [73], FTO-MC4R (FTO rs1121980; FTO rs9939609; MC4R rs17782313) [77], ADIPOQ (rs1501299 T; rs2241766 C; rs1063539 A/C) [71,80,81], IGF-I (CA)19 allele [87], and PR (rs10895068 A) [94]. In contrast, other polymorphisms of obesityrelated genes exert a protective effect (e.g., LEPR*6920A, associated with a decreased risk of BC in women with BBD [67]; LEP-2548G/G, related to the expression of low leptin mRNA levels [70]; and LEPR SNP rs11585329 [622G.T]) and have been associated with improved DFS in women with early-stage BC [71].…”

Section: Obese Women At Risk Of Bcmentioning

confidence: 99%

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Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

et al. 2016

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Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-a, interleukin-6, and prostaglandin E 2 , insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development.The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies. The Oncologist 2016;21:404-417 Implications for Practice: Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk.The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.

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Section: Igf-i Snpsmentioning

confidence: 92%

Section: Leptin and Leptin Receptor Single Nucleotide Polymorphismsmentioning

confidence: 99%

Section: Pik3ca Snpsmentioning

confidence: 99%

Section: Obese Women At Risk Of Bcmentioning

confidence: 99%

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Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

et al. 2016

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“…tumor development and its progression in the case of malignant disease). Some of the established, currently investigated, and potential therapeutic target molecules include: insulin-like growth factor 1 receptor (IGF-1R) [4][5][6][7] ; mechanistic target of rapamycin (mTOR) [8][9][10] ; tyrosine kinases (TKs), such as platelet-derived growth factor receptor (PDGFR) [11,12] and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) [12] ; epidermal growth factor receptors (EGFRs) [13][14][15] ; vascular endothelial growth factor receptors (VEGFRs) [16] ; poly (ADP ribose) polymerase 1 (PARP-1) [17][18][19] ; phosphatidylinositol 3-kinase (PI3K) [17,20] Aurora A [21] ; human epidermal growth factor receptor 2 (HER2) [22,23] , and Raf/MEK [24] .…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics

Abubakar

Gan

2016

Oncology

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The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effectsand inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed.

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Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer

Jing

Wei

et al. 2018

Intl Journal of Cancer

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Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

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Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

Cited by 23 publications

References 33 publications

Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer

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