TY - JOUR
T1 - Comprehensive exome analysis of immunocompetent metastatic head and neck cancer models reveals patient relevant landscapes
AU - Li, Hui
AU - Ngan, Hoi Lam
AU - Liu, Yuchen
AU - Chan, Helen Hoi Yin
AU - Poon, Peony Hiu Yan
AU - Yeung, Chun Kit
AU - Peng, Yibing
AU - Lam, Wai Yip
AU - Li, Benjamin Xiaoyi
AU - He, Yukai
AU - Lui, Vivian Wai Yan
N1 - Funding Information:
Conflicts of Interest: V.W.Y.L. received research funding from the University-Industry Collaboration Program (UIM/329; from the Innovation and Technology Fund, Hong Kong government, and Lee’s Pharmaceutical (HK) Limited) in 2018–2020), and served as a scientific consultant for Novartis Pharmaceutical (Hong Kong SAR, China) Limited (October 2015 to October 2016). B.X.L. and W.Y.L. are from Lee’s Pharmaceutical (HK) Limited, but they have no conflicts of interest in this study. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Funding Information:
Funding: This research was funded by the University-Industry Collaboration Program (UIM/329; Innovation and Technology Fund, Hong Kong government, Hong Kong SAR, China, and Lee’s Pharmaceutical (HK) Ltd.). V.W.Y.L. also received research funding from the General Research Fund (#17114814, #17121616, #14168517), Research Impact Fund (#R4015-19F, #R4017-18); the Health and Medical Research Fund (HMRF#15160691, the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region, China); and the Hong Kong Cancer Fund, Hong Kong SAR, China. Y.L. received funding supports (Postdoctoral Hub PH-ITF Ref.: PiH/052/18 of UIM/329) from the Innovation and Technology Fund, Hong Kong government. V.W.Y.L. and Y.L. also received research funding from the Lee Hysan Foundation Research Grant and Endowment Fund Research Grant Schemes 2018–2019 (CA11281, V.W.Y.L.) and 2019–2020 (CA11286, V.W.Y.L.), United College, the Chinese University of Hong Kong, Hong Kong SAR, China.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/10
Y1 - 2020/10
N2 - Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures—Trp53, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapyand invasion/metastasis-related questions in host immunity contexts.
AB - Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures—Trp53, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapyand invasion/metastasis-related questions in host immunity contexts.
KW - 5 immunocompetent metastatic HNC models
KW - AT-84
KW - SCC VII
KW - Utility analyses
KW - Whole-exome sequencing analysis
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U2 - 10.3390/cancers12102935
DO - 10.3390/cancers12102935
M3 - Article
AN - SCOPUS:85092492945
SN - 2072-6694
VL - 12
SP - 1
EP - 19
JO - Cancers
JF - Cancers
IS - 10
M1 - 2935
ER -