TY - JOUR
T1 - The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma
AU - Caso, Raul
AU - Sanchez-Vega, Francisco
AU - Tan, Kay See
AU - Mastrogiacomo, Brooke
AU - Zhou, Jian
AU - Jones, Gregory D.
AU - Nguyen, Bastien
AU - Schultz, Nikolaus
AU - Connolly, James G.
AU - Brandt, Whitney S.
AU - Bott, Matthew J.
AU - Rocco, Gaetano
AU - Molena, Daniela
AU - Isbell, James M.
AU - Liu, Yuan
AU - Mayo, Marty W.
AU - Adusumilli, Prasad S.
AU - Travis, William D.
AU - Jones, David R.
N1 - Publisher Copyright:
© 2020 International Association for the Study of Lung Cancer
PY - 2020/12
Y1 - 2020/12
N2 - Introduction: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD). Methods: We identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection. Results: MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049). Conclusions: These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
AB - Introduction: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD). Methods: We identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection. Results: MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049). Conclusions: These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
KW - Histologic subtypes
KW - Lung adenocarcinoma
KW - Next-generation sequencing
KW - Tumor genomic profiling
UR - http://www.scopus.com/inward/record.url?scp=85090019483&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2020.08.005
DO - 10.1016/j.jtho.2020.08.005
M3 - Article
C2 - 32791233
AN - SCOPUS:85090019483
SN - 1556-0864
VL - 15
SP - 1844
EP - 1856
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 12
ER -