The genetic variants in the PTEN/PI3K/AKT pathway predict susceptibility and CE(A)F chemotherapy response to breast cancer and clinical outcomes

Abstract

The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0.043, P=0.002, P=0.008, respectively), and the C allele carriers had a 1.224-fold significantly increased risk of developing BC (P= 0.003). Moreover, a higher frequency of AKT rs2494752 AG genotype was observed among cases (P=0.045). Individuals harboring rs2494752 AG/AA genotype had a vital increased susceptibility to BC in the dominant model (P=0.039). More importantly, AKT1 rs2494752 GG genotype showed significantly rates of response to NCT chemotherapy (P=0.048). Furthermore, AKT1 rs2494752 AG genotype carriers showed significantly shorter DFS time, and GG genotype as the independent prognostic factor (DFS: adjusted HR=1.523, 95% CI=1.012-2.293, P=0.044; OS: adjusted HR=2.321, 95% CI=1.281-4.204, P=0.005). Moreover, MDR analysis consistently revealed that the combination of 3 selected SNPs and 7 known risk factors represented the best model to predicting BC prognosis. The luciferase assay showed that the G allele of rs2494752 significantly increased AKT1 promoter activity. These results suggest that PTEN rs701848 and AKT1 rs2494752 polymorphisms might be a candidate pharmacogenomic factor to assess the susceptibility of BC and response and prognosis prediction for interindividualized CE(A)F chemotherapy in BC patients.

Association of Menopausal Status, Expression of Progesterone Receptor and Ki67 to the Clinical Response to Neoadjuvant Chemotherapy in Luminal Breast Cancer

“…23,26 Tumors within the same molecular subtype are heterogeneous, and, although the reasons for these differences are not clear, recent evidence suggests that tumors in younger patients show higher expression of genes related to mammary stem cells and deregulation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, which can con-tribute to endocrine therapy resistance and chemosensitivity in ER-positive tumors. [27][28][29] Tumors with lower PR expression had a higher probability of achieving cCR. In fact, it has been shown that PR expression in ER-positive tumors is associated with less aggressive phenotypes, and that tumors with lower PR expression may be less dependent on ER pathway signaling and show upregulation of the PI3K pathway.…”

Single nucleotide polymorphisms rs701848 and rs2735343 in PTEN increases cancer risks in an Asian population

“…We then assessed the remaining 53 reports in greater detail and excluded 35 articles that did not satisfy the eligibility criteria. Finally, 18 eligible case-control studies were included in our meta-analysis [ 20 – 37 ] (Figure 1 , Table 1 ). Moreover, we analyzed the data of each SNP independently in studies that investigated both rs701848 and rs2735343 SNPs [ 23 , 24 , 32 , 33 ].…”

“…Our conclusion was different from Ma's study that investigated 206 ESCC cases and controls each and concluded that the rs701848 CC genotype was not associated with ESCC risk [ 24 ]. We performed subgroup analysis and did not find correlation between rs701848 and increased risk of other cancers [ 20 , 21 , 25 , 33 , 35 ]. Our results also showed that rs2735343 GG genotype was associated with increased cancer risk supporting Jang's [ 23 ] and Ma's [ 24 ] findings.…”

“…The relationship between cancer risk and two PTEN SNPs, rs701848 and rs2735343 is controversial. The rs701848 SNP is associated with increased risk of breast cancer (BC) [ 20 ], renal cell cancer (RCC) [ 21 ], colorectal cancer (CRC) [ 22 ], and esophageal squamous cell cancer (ESCC) [ 23 ]. However, there are contradictory reports that show no correlation between rs701848 and the risk of ESCC [ 24 ] and hepatocellular carcinoma (HCC) [ 25 ].…”

Long non‐coding RNAs in cancer: Another layer of complexity

“…Other lncRNAs have been described to participate in the regulation of the PI3K/Akt pathway. HOTAIR has been related to the methylation of the tumor suppressor gene PTEN , and it is well known that PTEN antagonizes PI3K . Therefore, loss of PTEN function allows the over‐activation of Akt.…”