Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors

Motohiro Izumi,Yoko Tani,Koichi Ogawa,Tetsuya Watanabe,Kazuhisa Asai,Jun Oyanagi,Masahiko Ohsawa,Shigeki Mitsuoka,Kenji Sawa,Nobuyuki Yamamoto,Hiroyasu Kaneda,Mitsuru Fukui,Tomoya Kawaguchi,Yasuhiro Koh,Tomohiro Suzumura,Yoshiya Matsumoto

doi:10.1038/s41598-021-83609-y

Motohiro Izumi, Yoko Tani + Show 14 more

Open Access

https://doi.org/10.1038/s41598-021-83609-y

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Abstract

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Highlights

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors
Epidermal growth factor receptor (EGFR) mutations are more frequently found in female patients who are never smokers and who have adenocarcinoma histology, whereas KRAS mutations are more common in adenocarcinoma patients who are s mokers6–8
We focused on multiple primary lung cancers (MPLCs), which occur in a patient exposed to the identical risk factors and systemic reactions, including the immune response

Summary

Introduction

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Another study suggested that the majority of cancer risk is due to bad luck, with random mutations arising during DNA replication in normal, noncancerous stem c ells10 These previous studies analysed patients with different molecular and clinical backgrounds, and so were hindered by the problem that various factors are intricately intertwined. We focused on multiple primary lung cancers (MPLCs), which occur in a patient exposed to the identical risk factors and systemic reactions, including the immune response. This focus allowed us to elucidate the relationships between genetic mutations and non-intrinsic factors. Array comparative genomic hybridisation (CGH), histological subtyping, and imaging features are powerful tools to differentiate MPLC from intrapulmonary metastasis

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