Abstract 3626: Genomic evolutionary patterns in matched pre-invasive and invasive lung disease in TRACERx
Authors: Zhai Haoran , Puttick Clare , Moore David A. , Dietzen Michelle , Ward Sophia , Bakir Maise Al , Watkins Thomas , Rowan Andrew , Veeriah Selvaraju , Hynds Robert , Pich Oriol , Kanu Nnennaya ,   TRACERx Consortium, McGranahan Nicholas , Swanton Charles , Jamal-Hanjani Mariam 
Published: June 2022

Abstract
Introduction: The genomic landscape of pre-invasive lung disease, including AAH/AIS/MIA (atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive carcinoma) and squamous CIS (carcinoma in situ) which are considered to be precursors to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), has been profiled to a limited degree, due to the lack of matched samples within the same patient. Using TRACERx study we investigated the phylogenetic evolutionary patterns between matched pre-invasive and invasive lesions.
Methods: Post-operative pathology reports for 746 primary invasive tumors collected within TRACERx were screened to identify pre-invasive lesions that had been resected at the time of primary surgery. 50 pre-invasive lesions (21 AAH, 7 AIS, 6 MIA, 16 CIS) from 36 pts were subjected to whole exome sequencing with 119 matched tumor regions from 22 LUAD, 13 LUSC and 1 pleomorphic carcinoma. Phylogenetic relationships between pre-invasive and invasive lesions, timing of clonal divergence, mutational processes were investigated.
Results: Two major types of phylogenetic relationships were identified based on whether pre-invasive and invasive lesions shared a somatic common ancestor (SCA group; 7/22 LUAD, 11/13 LUSC) or not (non-SCA group; 15/22 LUAD, 2/13 LUSC, 1/1 pleomorphic carcinoma). Within SCA group, two evolutionary patterns were identified based on whether only clonal mutations or clonal and subclonal mutations were shared between pre-invasive and invasive lesions. 3/16 SCA pre-invasive lesions from ex-smokers were found to diverge from the invasive tumor years prior to diagnosis. Compared with non-SCA, SCA pre-invasive lesions harbored elevated mutational burden, APOBEC mutagenesis, chromosomal instability featured by increased loss of heterozygosity and somatic copy number alterations (SCNAs). Whole genome doubling was only detected in SCA pre-invasive lesions. In SCA LUAD, 3/7 exhibited clonal TP53 mutations, 3/7 exhibited clonal co-mutations of KEAP1 and STK11. In 5/15 non-SCA LUADs harboring a KRAS mutation, convergent KRAS mutation was detected in 4 matched pre-invasive and invasive lesions. Clonal focal gains on 3q21-29 (containing PIK3CA, ATR, SOX2) were detected in 10/11 SCA LUSC, suggesting that 3q gains may represent early events in tumor initiation. In the non-SCA group, convergent SCNAs encompassing oncogenes (PIK3CA, SOX2, FGFR3) or tumor suppressor genes (STK11, KEAP1, MGA) were detected.
Conclusions: We demonstrate that matched pre-invasive and invasive lesions fall in two distinct phylogenetic evolutionary groups: those that have a shared somatic common ancestor and those that do not. SCA pre-invasive lesions exhibit elevated APOBEC mutagenesis and chromosomal instability, shedding some light on the process of malignant transformation.
Citation Format: Haoran Zhai, Clare Puttick, David A. Moore, Michelle Dietzen, Sophia Ward, Maise Al Bakir, Thomas Watkins, Andrew Rowan, Selvaraju Veeriah, Robert Hynds, Oriol Pich, Nnennaya Kanu, TRACERx Consortium, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. Genomic evolutionary patterns in matched pre-invasive and invasive lung disease in TRACERx [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3626.