Never Smokers With Lung Cancer May Have One of Three Molecular Subtypes

January 26, 2022 by Elisa Becze BA, ELS, Editor

Most lung cancers in patients who have no smoking history are the result of natural genetic variants in the body that can be classified into one of three molecular subtypes, researchers reported in study ( finding published in Nature Genetics.

In the large epidemiologic study, researchers used whole­genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer: 189 adenocarcinomas, 36 carcinoids, and 7 tumors of other types. The patients had not yet undergone treatment for their cancer.

They found characteristics that could group the tumors into three different subtypes, which the researchers named piano, mezzo-forte, and forte. Piano was the most common subtype in never smokers. A slow-growing tumor rarely diagnosed in smokers, piano subtypes are characterized by somatic UBA1 variants, germline AR variants, and stem cell–like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, and frequent KRAS variations. The other subtypes are characterized by specific amplifications and EGFR variants (mezzo-forte) and whole-genome doubling (forte).

They also linked certain genetic signatures to predictive outcomes: five genomic variants in the receptor tyrosine kinase and Ras pathway independently doubled mortality.

“This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers,” the researchers said ( “What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes. In the future we may be able to have different treatments based on these subtypes.”

The field of genomics is revolutionizing cancer prevention, diagnosis, treatment, and nursing care. Listen to a comprehensive overview on the Oncology Nursing Podcast Episode 156: The History of Genomics in Cancer Care (

Copyright © 2022 by the Oncology Nursing Society. User has permission to print one copy for personal or unit-based educational use. Contact for quantity reprints or permission to adapt, excerpt, post online, or reuse ONS Voice content for any other purpose.