Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma

Jang, Kiseok; Song, Young Soo; Jang, Si‐Hyong; Min, Kyueng‐Whan; Na, Woong; Jang, Sang Ock; Jun, Young Jin; Lee, Kang Hong; Choi, Dongho; Paik, Seung Sam

doi:10.1111/j.1365-2559.2009.03468.x

Cited by 70 publications

(68 citation statements)

References 38 publications

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“…31,48 Previous studies have shown that loss of PTEN nuclear expression and BRAF mutations were associated with poor clinical outcome while the prognostic significance of PIK3CA and KRAS mutations in colorectal cancer remains elusive. 24,[49][50][51][52][53][54][55][56][57][58] In our series, loss of PTEN nuclear expression in primary tumors and the PIK3CA mutations in metastases were associated with shorter overall survival (Supplementary Table S2); however, neither PTEN expression nor PIK3CA mutations were emerged as independent prognostic factors in multivariate analysis ( Table 4). Activation of RAS/PI3K signaling network by mutation of at least one of the BRAF, KRAS and PI3KCA was associated with shorter survival, as previously reported by Barault et al (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Intensity of immunoreactivity for both antibodies was determined as 0, negative; 1, weak; 2, moderate; and 3, strong. As regards the interpretation of PTEN cytoplasmic expression, one, two or three additional points were attributed if the percentage of positive cells was o25%, 25-50% or450%; tumors with a score o4 were considered to have loss of PTEN cytoplasmic expression.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

et al. 2013

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Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations. PIK3CA exon 9 mutations in primary tumors and loss of PTEN nuclear expression in metastases correlated with KRAS mutations. KRAS wild-type status in primary tumors was associated with loss of PTEN cytoplasmic expression and high gene copy number of MET. Survival and clinical data were available for 68 patients. The multiple regression analysis revealed that the right-sided tumor localization and overexpression of MET were associated with shorter overall survival.

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

et al. 2013

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“…[16][17][18] and less than 5% microsatellite stable (MSS) tumors (19,20). However, associations with advanced tumor stage and poor outcome are less certain (11,(21)(22)(23)(24). PIK3CA mutations have been reported to be more frequent in women (8,25,26), proximal (26), welldifferentiated (5), and mucinous tumors (5), but these findings have not been consistent (4,8,27,28).…”

Section: Introductionmentioning

confidence: 99%

PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

Day

Jorissen

Lipton

et al. 2013

Clinical Cancer Research

111

115

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Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial.Experimental Design: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n ¼ 5,594).Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status.Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF mut ), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS mut ) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes.

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“…PTEN, which is located at human chromosome 10q23, has been identified as a tumor suppressor gene and an important negative regulator of the PI3K-AKT-mTOR signaling pathway that promotes cell proliferation and inhibits apoptosis (31). Inactivation of PTEN by mutation, deletion and promoter hypermethylation has been demonstrated in a range of cancer types, including lung, breast, prostate and esophageal carcinomas (31-35).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma

Sun

Song

et al. 2012

Oncology Letters

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Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma

Abstract: Nuclear PTEN expression gradually decrease during the normal-adenoma-adenocarcinoma-metastasis sequence, which suggests an important role for PTEN in carcinogenesis. Moreover, loss of nuclear PTEN expression was a marker of poor clinical outcome in patients with stage II colorectal cancer.

Cited by 70 publications

References 38 publications

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma

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