Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response.

Cold Spring Harber Molecular Case Studies - November 2016

Biswas et al. describe an “exceptional responder” lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for 7 years while undergoing single or combination ERBB2-directed therapies. Whole-genome, whole-exome, and high-coverage ion-torrent targeted sequencing were used to demonstrate extreme genomic heterogeneity between the lung and lymph node metastatic sites with only ∼1% similarity of somatic alterations between the lung and lymph node sites. However, one novel translocation, PLAG1-ACTA2, was present in both sites, and in all biopsies and autopsy samples. The Circos plot (center) depicts the degree of genomic heterogeneity seen within this patient. Chromosome numbers and cytobands are indicated in the outer circle, and within the second circle translocation breakpoints (dark blue, lung tumor only; orange, lymph node only; magenta, both) and genes with key nonsynonymous mutations, preceded by dots (black, lung tumor only; green, lymph node only; magenta, both) are shown. Within the two inner circles (lung tumor, outer; lymph node, inner), copy-number variations (CNVs) are shown as histogram plots (green, gain; red, loss). Dual-color fluorescence in situ hybridization (FISH) images of the PLAG1-ACTA2 translocation common to both metastatic sites are shown above (PLAG1-ACTA2 fusion) and below (ACTA2 break apart) the Circos plot: PLAG1-ACTA2 gene fusion (5′PLAG1, gold; 3′ACTA2, red fluorescence signals) present in 2011 lung adenocarcinoma wedge (L), 2011 and 2013 right cervical lymph node biopsies, (LN1 and LN2), 2015 autopsy material (LN6 and LN7), and ACTA2 break apart seen as split 5′ (green) and 3′ (red) fluorescence in L and LN2. (For detail, see Biswas et al., this issue; doi: 10.1101/mcs.a001263.)

Lab/Branch/Program: 
Thoracic Surgery Branch
Citation: 

Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001263. PMID:27900369

Published Date: 
November, 2016