Research Papers:

Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

Einav Simon, Tova Bick, Shada Sarji, Talia Shentzer, Elad Prinz, Liza Yehiam, Edmond Sabo, Ofer Ben-Izhak and Dov Hershkovitz _

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Oncotarget. 2017; 8:45736-45749. https://doi.org/10.18632/oncotarget.17399

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Einav Simon1, Tova Bick1, Shada Sarji1, Talia Shentzer2, Elad Prinz3, Liza Yehiam3, Edmond Sabo1,3, Ofer Ben-Izhak1,3 and Dov Hershkovitz4,5

1Institute of Pathology, Rambam Health Care Campus, Haifa, Israel

2Institute of Oncology, Rambam Health Care Campus, Haifa, Israel

3The Technion Integrated Cancer Center, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

4Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

5Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Correspondence to:

Dov Hershkovitz, email: [email protected]

Keywords: sub-clonality, lung adenocarcinoma, KRAS, EGFR, evolution

Received: February 21, 2017    Accepted: April 05, 2017    Published: April 24, 2017


Genetic sub-clonality has been described in multiple malignancies, however the presence of sub-clonality for major drivers in lung adenocarcinoma and its clinical significance is a subject under debate. Using molecular and morphometric approach, 347 lung adenocarcinoma samples were analyzed for KRAS and EGFR sub-clonality, which was further correlated with clinical and pathological variables.

KRAS and EGFR mutations were identified in 100 (29%) and 82 (23%) cases, respectively. One hundred and forty four KRAS or EGFR positive cases were also available for morphometric analysis, among which 37 (26%) were defined as sub-clonal. The presence of sub-clonality was associated with shorter survival time (p=0.02). Interestingly, cases with sub-clonality were also associated with earlier disease stage (89% vs 66% stage I disease in sub-clonal vs clonal cases, respectively, p=0.01) and less lymph node involvement (8% vs 25% in sub-clonal vs clonal cases, respectively, p=0.02). Our findings demonstrate the presence of sub-clonality for mutations in common drivers in lung adenocarcinoma and link it both to earlier disease stage and to poor survival. These findings are in line with the different evolutionary models that can present with genetic sub-clonality.

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