Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer

被引：197

作者：

Joanito, Ignasius ^{[1
]}

Wirapati, Pratyaksha ^{[2
]}

Zhao, Nancy ^{[1
]}

Nawaz, Zahid ^{[1
]}

Yeo, Grace ^{[1
]}

Lee, Fiona ^{[1
,3
]}

Eng, Christine L. P. ^{[1
,3
]}

Macalinao, Dominique Camat ^{[3
]}

Kahraman, Merve ^{[1
]}

Srinivasan, Harini ^{[1
,3
]}

Lakshmanan, Vairavan ^{[3
]}

Verbandt, Sara ^{[4
]}

Tsantoulis, Petros ^{[5
,6
]}

Gunn, Nicole ^{[3
]}

Venkatesh, Prasanna Nori ^{[1
]}

Poh, Zhong Wee ^{[1
,7
]}

Nahar, Rahul ^{[8
]}

Oh, Hsueh Ling Janice ^{[8
]}

Loo, Jia Min ^{[1
]}

Chia, Shumei ^{[1
]}

Cheow, Lih Feng ^{[9
]}

Cheruba, Elsie ^{[9
]}

Wong, Michael Thomas ^{[8
]}

Kua, Lindsay ^{[3
]}

Chua, Clarinda ^{[3
]}

Nguyen, Andy ^{[10
]}

Golovan, Justin ^{[10
]}

Gan, Anna ^{[1
]}

Lim, Wan-Jun ^{[3
]}

Guo, Yu Amanda ^{[1
]}

Yap, Choon Kong ^{[1
]}

Tay, Brenda ^{[3
]}

Hong, Yourae ^{[11
]}

Chong, Dawn Qingqing ^{[3
,7
]}

Chok, Aik-Yong ^{[12
]}

Park, Woong-Yang ^{[11
]}

Han, Shuting ^{[3
]}

Chang, Mei Huan ^{[12
]}

Seow-En, Isaac ^{[12
]}

Fu, Cherylin ^{[12
]}

Mathew, Ronnie ^{[12
]}

Toh, Ee-Lin ^{[12
,13
]}

Hong, Lewis Z. ^{[8
]}

Skanderup, Anders Jacobsen ^{[1
]}

DasGupta, Ramanuj ^{[1
]}

Ong, Chin-Ann Johnny ^{[14
,15
,16
,17
,18
,19
]}

Lim, Kiat Hon ^{[20
]}

Tan, Emile K. W. ^{[12
]}

Koo, Si-Lin ^{[3
]}

Leow, Wei Qiang ^{[20
]}

机构：

[1] ASTAR, Genome Inst Singapore, Singapore, Singapore

[2] Swiss Inst Bioinformat, Bioinformat Core Facil, Lausanne, Switzerland

[3] Natl Canc Ctr, Singapore, Singapore

[4] Katholieke Univ Leuven, Mol Digest Oncol, Dept Oncol, Leuven, Belgium

[5] Hop Univ Geneve, Geneva, Switzerland

[6] Univ Geneva, Geneva, Switzerland

[7] Duke Natl Univ Singapore, Med Sch, Singapore, Singapore

[8] MSD Int GmbH, Singapore Branch, Singapore, Singapore

[9] Natl Univ Singapore, Singapore, Singapore

[10] NantOm, Rockville, MD USA

[11] Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea

[12] Singapore Gen Hosp, Dept Colorectal Surg, Singapore, Singapore

[13] EL Toh Colorectal & Minimally Invas Surg, Singapore, Singapore

[14] Natl Canc Ctr Singapore, Div Surg & Surg Oncol, Dept Sarcoma Peritoneal & Rare Tumours SPRinT, Singapore, Singapore

[15] Singapore Gen Hosp, Div Surg & Surg Oncol, Dept Sarcoma Peritoneal & Rare Tumours SPRinT, Singapore, Singapore

[16] Natl Canc Ctr Singapore, Div Med Sci, Lab Appl Human Genet, Singapore, Singapore

[17] Duke NUS Med Sch, SingHlth Duke NUS Oncol Acad Clin Program, Singapore, Singapore

[18] Duke NUS Med Sch, SingHlth Duke NUS Surg Acad Clin Program, Singapore, Singapore

[19] A STAR Res Ent, Inst Mol & Cell Biol, Singapore, Singapore

[20] Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore

来源：

NATURE GENETICS | 2022年 / 54卷 / 07期

关键词：

SUBTYPES; PROGNOSIS; PATHWAY; IMMUNE; KRAS; MUTATIONS; SIGNATURE; PROGRAMS; RELEVANT; GENES;

D O I：

10.1038/s41588-022-01100-4

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis. The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined 'IMF' classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F).

引用

页码：963 / +

页数：35

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