What genetic factor may explain why non–small cell lung cancer (NSCLC) often fails to respond to treatment?

Updated: Jul 15, 2021
  • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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Other molecular abnormalities found in NSCLC include mutations in the oncogenes c-myc and c-raf and in the tumor suppressor genes retinoblastoma (Rb) and p53.

Two studies have documented early and extensive mutations in lung cancers that result in pronounced intratumor heterogeneity by the time these cancers manifest clinically—thus helping to explain why these cases so often fail to respond to treatment. A study by Zhang and colleagues identified 20 of 21 known cancer gene mutations in all regions of 11 localized lung adenocarcinomas. On follow-up, patients who had postsurgical relapse had significantly larger fractions of subclonal mutations in their primary tumors. [9]

Similarly, a study by de Bruin and colleagues in seven operable NSCLCs determined that there was a long period of tumor latency between early mutations and clinical symptoms, which appeared after new mutations triggered rapid disease growth. In some former smokers, the initial mutations dated back to when they were smoking cigarettes, two decades earlier. Over time, however, those mutations became less important, with more recent mutations resulting from a new process controlled by a protein called APOBEC. [10]

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