Diverse tumour susceptibility in Collaborative Cross mice

Identification of a new mouse model for human gastric tumourigenesis

Pin Wang, Yunshan Wang, Sasha A. Langley, Yan Xia Zhou, Kuang-Yu Jen, Qi Sun, Colin Brislawn, Carolina M. Rojas, Kimberly L. Wahl, Ting Wang, Xiangshan Fan, Janet K. Jansson, Susan E. Celniker, Xiaoping Zou, David W. Threadgill, Antoine M. Snijders, Jian Hua Mao

Research output: Contribution to journalArticle

Abstract

Objective: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. Design: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. Results: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκ b1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. Conclusions: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

Original languageEnglish (US)
JournalGut
DOIs
StatePublished - Jan 1 2019

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Stomach
Neoplasms
Genes
RNA Sequence Analysis
Survival
Stomach Neoplasms
Adenocarcinoma
Incidence
Kaplan-Meier Estimate
Genome
Staining and Labeling
Gene Expression
Population
Proteins

Keywords

  • collaborative cross
  • gastric cancer
  • mouse model
  • tumor susceptibility

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Diverse tumour susceptibility in Collaborative Cross mice : Identification of a new mouse model for human gastric tumourigenesis. / Wang, Pin; Wang, Yunshan; Langley, Sasha A.; Zhou, Yan Xia; Jen, Kuang-Yu; Sun, Qi; Brislawn, Colin; Rojas, Carolina M.; Wahl, Kimberly L.; Wang, Ting; Fan, Xiangshan; Jansson, Janet K.; Celniker, Susan E.; Zou, Xiaoping; Threadgill, David W.; Snijders, Antoine M.; Mao, Jian Hua.

In: Gut, 01.01.2019.

Research output: Contribution to journalArticle

Wang, P, Wang, Y, Langley, SA, Zhou, YX, Jen, K-Y, Sun, Q, Brislawn, C, Rojas, CM, Wahl, KL, Wang, T, Fan, X, Jansson, JK, Celniker, SE, Zou, X, Threadgill, DW, Snijders, AM & Mao, JH 2019, 'Diverse tumour susceptibility in Collaborative Cross mice: Identification of a new mouse model for human gastric tumourigenesis', Gut. https://doi.org/10.1136/gutjnl-2018-316691
Wang, Pin ; Wang, Yunshan ; Langley, Sasha A. ; Zhou, Yan Xia ; Jen, Kuang-Yu ; Sun, Qi ; Brislawn, Colin ; Rojas, Carolina M. ; Wahl, Kimberly L. ; Wang, Ting ; Fan, Xiangshan ; Jansson, Janet K. ; Celniker, Susan E. ; Zou, Xiaoping ; Threadgill, David W. ; Snijders, Antoine M. ; Mao, Jian Hua. / Diverse tumour susceptibility in Collaborative Cross mice : Identification of a new mouse model for human gastric tumourigenesis. In: Gut. 2019.
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abstract = "Objective: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. Design: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. Results: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40{\%} of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκ b1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. Conclusions: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.",
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author = "Pin Wang and Yunshan Wang and Langley, {Sasha A.} and Zhou, {Yan Xia} and Kuang-Yu Jen and Qi Sun and Colin Brislawn and Rojas, {Carolina M.} and Wahl, {Kimberly L.} and Ting Wang and Xiangshan Fan and Jansson, {Janet K.} and Celniker, {Susan E.} and Xiaoping Zou and Threadgill, {David W.} and Snijders, {Antoine M.} and Mao, {Jian Hua}",
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T1 - Diverse tumour susceptibility in Collaborative Cross mice

T2 - Identification of a new mouse model for human gastric tumourigenesis

AU - Wang, Pin

AU - Wang, Yunshan

AU - Langley, Sasha A.

AU - Zhou, Yan Xia

AU - Jen, Kuang-Yu

AU - Sun, Qi

AU - Brislawn, Colin

AU - Rojas, Carolina M.

AU - Wahl, Kimberly L.

AU - Wang, Ting

AU - Fan, Xiangshan

AU - Jansson, Janet K.

AU - Celniker, Susan E.

AU - Zou, Xiaoping

AU - Threadgill, David W.

AU - Snijders, Antoine M.

AU - Mao, Jian Hua

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. Design: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. Results: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκ b1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. Conclusions: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

AB - Objective: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. Design: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. Results: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκ b1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. Conclusions: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

KW - collaborative cross

KW - gastric cancer

KW - mouse model

KW - tumor susceptibility

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