Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas

Woo, Tetsukan; Okihara, Koji; Yazawa, Takuya; Wada, Nobuyuki; Ogawa, Norio; Ishiwa, Naoki; Tajiri, Michihiko; Rino, Yasushi; Kitamura, Hitoshi; Masuda, Munetaka

doi:10.1016/j.lungcan.2008.11.020

Cited by 99 publications

(120 citation statements)

References 41 publications

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“…In previous studies, the expression of CD133 was correlated with a poor prognosis in lung cancer (24). Similarly to other reports (24,25), our analysis indicated that CD133-positive tumors were associated with significantly worse outcomes in comparison to CD133-negative tumors. We therefore consider CD133 to be an appropriate CSC marker.…”

Section: Discussionsupporting

confidence: 88%

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma

Miyata

Oyama

Yoshimatsu

et al. 2017

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Abstract. Background/Aim: Aldehyde dehydrogenase-1A1 (ALDH1A1) and CD133 have been identified as markers of cancer stem cells (CSCsDespite continuous efforts to improve therapeutic response, lung cancer is the most common cause of cancer-related deaths in Japan, with adenocarcinoma by far the most common histology, accounting for nearly 70% of lung cancer cases (1). Cancer stem cells (CSCs) have the ability for selfrenewal and multipotently differentiate (2). CSCs may be highly resistant to chemotherapy and radiation, and be responsible for tumor initiation, progression and metastasis (3, 4). Accumulating evidence supports the existence of a CSC phenotype in human lung cancer (3, 5-7). The metabolic marker aldehyde dehydrogenase isoform 1A1 (ALDH1A1) and the cell-surface marker CD133 are reported to be markers of lung CSCs (3). We, therefore, investigated ALDH1A1 and CD133 expression in a retrospective cohort of 92 patients with lung adenocarcinoma. The objectives were to determine the association between ALDH1A1 and CD133 expression in lung adenocarcinoma, the relationship between their expression and the clinichopathological parameters, and the prognostic value of ALDH1A1 and CD133. Materials and MethodsPatient population and clinicopathological data. We examined a series of 154 Japanese patients with lung adenocarcinoma who underwent surgical treatment at Fukuoka-Wajiro Hospital, Fukuoka, Japan from 2006-2012. Ninety-two out of 154 (59.7%) patients were selected based on the following inclusion criteria: (i) no chemotherapy or radiotherapy before surgery, and (ii) the availability of an adequate paraffin block and clinicopathological data for the analysis. Follow-up information was obtained from the patients' records. Routinely collected clinicopathological data included age, gender, smoking history and pathological stage. There were 49 males (53%) and 43 females (47%), with a median age of 71 years (range=40-92 years) at the time of surgery; 43 (47%) patients were <70 years and 49 (53%) were ≥70 years of age. Half of the patients (n=46) had a smoking history. The pathological stages were: stage I, n=62 (67.4%); stage II, n=14 (15.2%); stage III, n=12 (13.0%); and stage IV, n=4 (4.4%) (TNM staging of lung cancer) (8). The median follow-up period was 1,702 days (range=4-3679 days). Recurrence was diagnosed by computed tomography alone or combined with positron-emission tomography.

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Section: Discussionsupporting

confidence: 88%

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma

Miyata

Oyama

Yoshimatsu

et al. 2017

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“…High expression of Ki-67 (cut-off above 10) is associated with worse survival in adenocarcinomas. 30 Solid pattern expressed higher levels of Ki-67 when compared to micropapillary (p = 0.0219), acinar (p = 0.0731) and mucinous (p = 0.068) patterns and we can hypothesize that solid pattern can have a worse biological behaviour, either reflecting an higher proliferation index or a particular differential origin or as already referred, bronchial development when without expression of either TTF1 and high weight molecular cytokeratin (CK 5, 6/CK5, 6, 18).…”

Section: Discussionmentioning

confidence: 99%

“…Gender and smoking habits have been significantly related with EGFR mutations. 2,3,30,39 The commonly reported EGFR mutation rate by PCR sequencing and fragment analyses in lung adenocarcinomas is around 20%. 40 Mutations are found in the first four exons of the TK domain of the EGFR gene.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings are similar to Kim et al study, who also realized that KRAS mutations are significantly related with smoking habits (p = 0.014) in a total rate of 30.8% in smokers while in non-smokers it was only 5.7%. 30,42 KRAS mutations have been associated with mucinous differentiation, goblet cell, poor differentiation adenocarcinomas and with solid patterns. 48---52 However in our cases we did find this mutation in acinar and lepidic patterns and in only one case with solid pattern.…”

Section: Discussionmentioning

confidence: 99%

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Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status

Sousa

Rodrigues

Silva

et al. 2015

Revista Portuguesa de Pneumologia (English Edition)

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Pulmonary adenocarcinomas are still in the process of achieving morphological, immunohistochemical and genetic standardization. The ATS/ERS/IASLC proposed classification for lung adenocarcinomas supports the value of the identification of histological patterns, specifically in biopsies.Thirty pulmonary adenocarcinomas were subjected to immunohistochemical study (CK7, CK5, 6, 18, CK20, TTF1, CD56, HER2, EGFR and Ki-67), FISH and PCR followed by sequencing and fragment analysis for EGFR, HER2 and KRAS.Solid pattern showed lower TTF1 and higher Ki-67 expression. TTF1 expression was higher in non-mucinous lepidic and micropapillary patterns when compared to acinar and solid and acinar, solid and mucinous respectively. Higher Ki67 expression was present in lepidic and solid patterns compared to mucinous. EGFR membranous staining had increasing expression from non-mucinous lepidic/BA pattern to solid pattern and micropapillary until acinar pattern. EGFR mutations, mainly in exon 19, were more frequent in females, together with non-smoking status, while KRAS exon 2 mutations were statistically more frequent in males, especially in solid pattern. FISH EGFR copy was correlated gross, with mutations. HER2 copy number was raised in female tumours without mutations, in all cases. Although EGFR and KRAS mutations are generally considered mutually exclusive, in rare cases they can coexist as it happened in one of this series, and was represented in acinar pattern with rates of 42.9% and 17.9%, respectively. EGFR mutations were more frequent in lepidic/BA and acinar patterns. Some cases showed different EGFR mutations.The differences identified between the adenocarcinoma patterns reinforce the need to carefully identify the patterns present, with implications in diagnosis and in pathogenic understanding. EGFR and KRAS mutational status can be determined in biopsies representing bronchial

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“…An IHC score 440 distinguished low from high expression of CAIX (Loncaster et al, 2001). Nuclear staining in more than 50% of positive cells for HIF-1a and a labeling index of Ki-67 X10% defined overexpression of both markers (Zhong et al, 1999;Woo et al, 2009). The overall score used for statistical analysis was the mean value from three spots of the same tumour.…”

Section: Automated Image Analysismentioning

confidence: 99%

High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer

et al. 2010

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BACKGROUND: Carbonic anhydrase IX (CAIX) is an enzyme upregulated by hypoxia during tumour development and progression. This study was conducted to assess if the expression of CAIX in tumour tissue and/or plasma can be a prognostic factor in patients with non-small cell lung cancer (NSCLC). METHODS: Tissue microarrays containing 555 NSCLC tissue samples were generated for quantification of CAIX expression. The plasma level of CAIX was determined by ELISA in 209 of these NSCLC patients and in 58 healthy individuals. The CAIX tissue immunostaining and plasma levels were correlated with clinicopathological factors and patient outcome. RESULTS: CAIX tissue overexpression correlated with shorter overall survival (OS) (P ¼ 0.05) and disease-specific survival (DSS) of patients (P ¼ 0.002). The CAIX plasma level was significantly higher in patients with NSCLC than in healthy individuals (Po0.001). A high level of CAIX in the plasma of patients was associated with shorter OS (Po0.001) and DSS (Po0.001), mostly in early stage I þ II NSCLC. Multivariate Cox analyses revealed that high CAIX tissue expression (P ¼ 0.002) was a factor of poor prognosis in patients with resectable NSCLC. In addition, a high CAIX plasma level was an independent variable predicting poor OS (Po0.001) in patients with NSCLC. CONCLUSION: High expression of CAIX in tumour tissue is a predictor of worse survival, and a high CAIX plasma level is an independent prognostic biomarker in patients with NSCLC, in particular in early-stage I þ II carcinomas.

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Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas

Cited by 99 publications

References 41 publications

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma

Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status

High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer

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