Genomic heterogeneity of multiple synchronous lung cancer

Abstract

Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events.

Figure 1. Similarity among different lesions rising from a single patient with MSLC based on somatic mutation analysis.

(a) Heatmap of validated mutations shared by 16 intra-thoracic adenocarcinomas of six patients with MSLC. The number of total mutations identified in each tumour (T) and the number of mutations shared by any pair of lesions are shown. Tumours from the same patients are identified by blue boxes. LN, lymph node metastasis. (b) Venn diagram illustrating the distributions of validated mutations in the 16 lesions. Shared mutations were defined as identical nucleotide substitutions at the same genomic coordinates.

Figure 2. Nonsynonymous point mutations and copy number changes in known cancer genes in 16 intra-thoracic lesions of six patients with MSLC.

Copy number changes were defined on the basis of segment log₂ ratios derived from microarray-based CGH, with log₂ ratios >0.3 categorized as copy number gains and log₂ ratios <−0.3 categorized as copy number losses. AA, amino acid; LN, lymph node metastasis; NA, not applicable; T, tumour number.