KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma

Rekhtman, Natasha; Ang, Daphne; Riely, Gregory J.; Ladanyi, Marc; Moreira, André L.

doi:10.1038/modpathol.2013.74

Cited by 102 publications

(91 citation statements)

References 52 publications

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“…For example, the metabolic region of EGFR1 tumors was smaller and had a lower SUV max than EGFR-tumors. Because of their low SUV uptake and smaller MTV, our results are consistent with the notion that EGFR mutants tend to be more indolent than other lung cancer types (39,40). In addition, 8 radiomic features were significantly associated with and predictive of EGFR mutation status, where InvDiffmomnor was the most predictive for EGFR mutation status and significantly outperformed the conventional measure MTV (P # 0.02).…”

Section: Discussionsupporting

confidence: 78%

Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non–Small Cell Lung Cancer

et al. 2016

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PET-based radiomics have been used to noninvasively quantify the metabolic tumor phenotypes; however, little is known about the relationship between these phenotypes and underlying somatic mutations. This study assessed the association and predictive power of 18 F-FDG PET-based radiomic features for somatic mutations in non-small cell lung cancer patients. Methods: Three hundred forty-eight non-small cell lung cancer patients underwent diagnostic 18 F-FDG PET scans and were tested for genetic mutations. Thirteen percent (44/348) and 28% (96/348) of patients were found to harbor epidermal growth factor receptor (EGFR) or Kristen rat sarcoma viral (KRAS) mutations, respectively. We evaluated 21 imaging features: 19 independent radiomic features quantifying phenotypic traits and 2 conventional features (metabolic tumor volume and maximum SUV). The association between imaging features and mutation status (e.g., EGFR-positive [EGFR1] vs. EGFR-negative) was assessed using the Wilcoxon rank-sum test. The ability of each imaging feature to predict mutation status was evaluated by the area under the receiver operating curve (AUC) and its significance was compared with a random guess (AUC 5 0.5) using the Noether test. All P values were corrected for multiple hypothesis testing by controlling the false-discovery rate (FDR Wilcoxon , FDR Noether ) with a significance threshold of 10%. Results: Eight radiomic features and both conventional features were significantly associated with EGFR mutation status (FDR Wilcoxon 5 0.01-0.10). One radiomic feature (normalized inverse difference moment) outperformed all other features in predicting EGFR mutation status (EGFR1 vs. EGFR-negative, AUC 5 0.67, FDR Noether 5 0.0032), as well as differentiating between KRAS-positive and EGFR1 (AUC 5 0.65, FDR Noether 5 0.05). None of the features was associated with or predictive of KRAS mutation status (KRAS-positive vs. KRAS-negative, AUC 5 0.50-0.54). Conclusion: Our results indicate that EGFR mutations may drive different metabolic tumor phenotypes that are captured in PET images, whereas KRAS-mutated tumors do not. This proof-of-concept study sheds light on genotype-phenotype interactions, using radiomics to capture and describe the phenotype, and may have potential for developing noninvasive imaging biomarkers for somatic mutations.

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Section: Discussionsupporting

confidence: 78%

Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non–Small Cell Lung Cancer

et al. 2016

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“…However, KRAS mutations were less frequently indicated in the acinar predominant subtype (P=0.002) and adenocarcinomas with lepidic component (P=0.047), which was in consistent with the report by Rekhtman et al (29).…”

Section: A B C D E Fsupporting

confidence: 82%

“…Wang et al (26) did not identify any significant differences in histological subtypes between the KRAS mutations and the wild-types; whereas, Yoshizawa et al (14) and Kakegawa et al (28) indicated that KRAS mutations were significantly associated with adenocarcinoma of mucinous tumor subtypes (P<0.001). Rekhtman et al (29) showed that KRAS mutations occurred more often in adenocarcinomas with a solid growth pattern (P=0.022).…”

Section: A B C D E Fmentioning

confidence: 99%

Association between the histological subtype of lung adenocarcinoma, EGFR/KRAS mutation status and the ALK rearrangement according to the novel IASLC/ATS/ERS classification

et al. 2016

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Abstract. The present study aimed to investigate the association between epidermal growth factor receptor (EGFR)/Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements and the morphological characteristics of lung adenocarcinoma (LAC), according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification in a large group of patients with primary LAC. A total of 200 patients with invasive LAC who had undergone complete resections at the Beijing Chest Hospital (Beijing, China) were randomly selected. The morphology of the samples was reassessed in 5% increments by two pathologists, according to the IASLC/ATS/ERS scheme. EGFR and KRAS mutations were tested by direct DNA sequencing. ALK rearrangements were screened by immunohistochemistry on a Benchmark XT stainer. The data revealed that EGFR and KRAS mutations, and ALK rearrangements were identified in 46.0% (92/200), 9.0% (18/200) and 11.5% (23/200) of the patients, respectively. The EGFR/KRAS mutations and ALK rearrangements were mostly exclusive. However, 1 patient exhibited the coexistence of the EGFR (at exon 20) and KRAS (codon 12) mutations, and another patient exhibited the coexistence of the EGFR mutation (at exon 21) and the ALK gene fusion. EGFR mutations were indicated to be closely associated with the acinar predominant (43/77; 55.8%; P=0.030) and papillary predominant (26/49; 53.1%; P=0.006) subtypes. KRAS mutations were more commonly associated with the solid predominant subtype (9/52; 17.3%; P=0.023) and invasive mucinous LAC (5/10; 50.0%; P=0.004), and less commonly associated with the acinar predominant subtype (1/77; 1.3%; P=0.002). ALK rearrangements more commonly occurred in the solid predominant subtype compared with other subtypes (13/52; 25%; P=0.002), and less commonly occurred in the papillary predominant subtype (1/49; 2.0%; P=0.004). Tumors harboring ALK rearrangements were characterized by signet-ring cell (7/9; 77.8%; P<0.0001) and cribriform (7/12; 58.3%; P<0.0001) patterns. The association between the mutation status and histological subtype in LAC was distinct. The predominant subtype according to the IASLC/ATS/ERS classification provided important information for gene mutations and integrated clinical findings to improve the treatment of LAC patients.

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“…14,15 Studies suggest that KRAS mutations are found in 17% to 37% of lung adenocarcinomas from white patients and 5% to 17% of lung adenocarcinomas from Asian patients. 13,[16][17][18][19] KRAS mutations are more frequently found in lung cancers from patients with heavy tobacco exposure, but they are also encountered among never-smokers with lung cancer. 20 Our study showed similar findings, with a 32% prevalence of KRAS mutation in our lung cancer series, including mutations in 83% of lung cancers from heavy smokers, but in only 8.5% of lung cancers from patients who were never-smokers.…”

Section: -13mentioning

confidence: 99%

Peripheral Lung Adenocarcinomas With KRAS Mutations Are More Likely to Invade Visceral Pleura

Raparia¹,

Villa

Raj

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Kirsten-RAS (KRAS) mutations play an important role in the carcinogenesis of a subset of lung adenocarcinomas and are associated with poorer prognosis.Objective.-To investigate the relationship of KRAS mutation status to the histologic subtype of adenocarcinoma according to the recent classification, patient demographics, tumor size, predominant histologic subtype, nodal status, and visceral pleural invasion, in an attempt to uncover the reason for the worse prognosis associated with KRAS mutation.Design.-A total of 187 consecutive resected lung adenocarcinomas from our institution from 2008 to 2011 that were diagnosed according to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification and screened for KRAS mutations were included in the study.Results.-A total of 32% of the adenocarcinomas harbored the KRAS mutation. The median age in the KRAS mutation group was 69 years (range, 43-86 years), and male to female ratio was 1:2.3. The proportion of heavy smokers was significantly higher in tumors with KRAS mutation compared with wild type (83% versus 62%; P ¼ .01). A total of 27% of tumors with KRAS mutation had pleural invasion versus 11% of tumors without KRAS mutation (P ¼ .009). A total of 59 tumor samples were positive for KRAS mutation (25 for G12C, 14 for G12A, 8 for G12V, 7 for G12D, 3 for G12S, and 1 for G12T), and only 3 tumors harbored codon 13 mutations (G13C). Two tumors had double mutations.Conclusions.-KRAS mutations are more common in heavy smokers, and lung adenocarcinomas with KRAS mutation are more likely to invade the visceral pleura. Increased frequency of visceral pleural invasion may explain in part the worse prognosis associated with KRAS mutations.

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KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma

Cited by 102 publications

References 52 publications

Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non–Small Cell Lung Cancer

Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non–Small Cell Lung Cancer

Association between the histological subtype of lung adenocarcinoma, EGFR/KRAS mutation status and the ALK rearrangement according to the novel IASLC/ATS/ERS classification

Peripheral Lung Adenocarcinomas With KRAS Mutations Are More Likely to Invade Visceral Pleura

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