Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer

Authors: Mingshan Liu, Yang Liu, Jiabo Di, Zhe Su, Hong Yang, Beihai Jiang, Zaozao Wang, Meng Zhuang, Fan Bai, Xiangqian Su

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors.

Methods

We sequenced nine tumor regions and 88 single cells from two rectal cancer patients with tumors of the same molecular classification and characterized their mutation profiles and somatic copy number alterations (SCNAs) at the multi-region and the single-cell levels.

Results

A variable extent of genomic heterogeneity was observed between the two patients, and the degree of ITH increased when analyzed on the single-cell level. We found that major SCNAs were early events in cancer development and inherited steadily. Single-cell sequencing revealed mutations and SCNAs which were hidden in bulk sequencing. In summary, we studied the ITH of rectal cancer at regional and single-cell resolution and demonstrated that variable heterogeneity existed in two patients. The mutational scenarios and SCNA profiles of two patients with treatment naïve from the same molecular subtype are quite different.

Conclusions

Our results suggest each tumor possesses its own architecture, which may result in different diagnosis, prognosis, and drug responses. Remarkable ITH exists in the two patients we have studied, providing a preliminary impression of ITH in rectal cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.CrossRef
3.
Tamas K, Walenkamp AM, de Vries EG, van Vugt MA, Beets-Tan RG, van Etten B, et al. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015;41:671–9.CrossRefPubMed
4.
Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med. 2015;21:751–9.CrossRefPubMedPubMedCentral
5.
Cao W, Wu W, Yan M, Tian F, Ma C, Zhang Q, et al. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma. Oncogene. 2015;4:e175.CrossRef
6.
Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet. 2014;46:225–33.CrossRefPubMedPubMedCentral
7.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.CrossRefPubMedPubMedCentral
8.
de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346:251–6.CrossRefPubMedPubMedCentral
9.
Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014;346:256–9.CrossRefPubMedPubMedCentral
10.
Ni X, Zhuo M, Su Z, Duan J, Gao Y, Wang Z, et al. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc Natl Acad Sci U S A. 2013;110:21083–8.CrossRefPubMedPubMedCentral
11.
12.
Wang Y, Waters J, Leung ML, Unruh A, Roh W, Shi X, et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature. 2014;512:155–60.CrossRefPubMedPubMedCentral
13.
Gao R, Davis A, McDonald TO, Sei E, Shi X, Wang Y, et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat Genet. 2016;48:1119–30.CrossRefPubMedPubMedCentral
14.
Yu C, Yu J, Yao X, WSu WKK, Lu Y, Tang S, et al. Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing. Cell Res. 2014;24:701–12.CrossRefPubMedPubMedCentral
15.
Zong C, Lu S, Chapman AR, Xie XS. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012;338:1622–6.CrossRefPubMedPubMedCentral
16.
17.
18.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.CrossRefPubMedPubMedCentral
19.
Josephidou M, Lynch AG, Tavaré S. multiSNV: a probabilistic approach for improving detection of somatic point mutations from multiple related tumour samples. Nucleic Acids Res. 2015;43:e61.CrossRefPubMedPubMedCentral
20.
Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila Melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6:80–92.CrossRef
21.
Xue R, Li R, Guo H, Guo L, Su Z, Ni X, et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with Hepatocellular carcinoma. Gastroenterology. 2016;150:998–1008.CrossRefPubMed
22.
Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 2011;28:2731–9.CrossRefPubMedPubMedCentral
23.
Favero F, Joshi T, Marquard AM, Birkbak NJ, Krzystanek M, Li Q, et al. Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data. Ann Oncol. 2015;26:64–70.CrossRefPubMed
24.
Cai X, Evrony GD, Lehmann HS, Elhosary PC, Mehta BK, Poduri A, et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 2014;8:1280–9.CrossRefPubMedPubMedCentral
25.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4:44–57.CrossRef
26.
Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13.CrossRef
27.
28.
Domingo E, Ramamoorthy R, Oukrif D, Rosmarin D, Presz M, Wang H, et al. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol. 2013;229:441–8.CrossRefPubMedPubMedCentral
29.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.CrossRefPubMedPubMedCentral
30.
Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.CrossRefPubMedPubMedCentral
31.
Schell MJ, Yang M, Teer JK, Lo FY, Madan A, Coppola D, et al. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun. 2016;7:11743.CrossRefPubMedPubMedCentral
32.
33.
Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9:862–73.CrossRefPubMed
34.
35.
Wang H, Liang L, Fang JY, Xu J. Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers. Oncogene. 2016;35:2011–9.CrossRefPubMed
36.
Gosens MJ, van Kempen LC, van de Velde CJ, van Krieken JH, Nagtegaal ID. Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol. 2007;20:221–32.CrossRefPubMed
37.
Huang L, Ma F, Chapman A, Lu S, Xie XS. Single-cell whole-genome amplification and sequencing: methodology and applications. Annu Rev Genomics Hum Genet. 2015;16:79–102.CrossRefPubMed
38.
Hou Y, Wu K, Shi X, Li F, Song L, Wu H, et al. Comparison of variations detection between whole-genome amplification methods used in single-cell resequencing. Gigascience. 2015;4:37.CrossRefPubMedPubMedCentral
39.
Reynolds AP, Richards G, de la Iglesia B, Rayward-Smith VJ. Clustering rules: a comparison of partitioning and hierarchical clustering algorithms. Journal of Mathematical Modelling and Algorithms. 2006;5:475–504.CrossRef
40.
Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15:453.CrossRefPubMedPubMedCentral
41.
Mayans O, van der Ven PFM, Wilm M, Mues A, Young P, Furst DO, et al. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature. 1998;395:863–9.CrossRefPubMed
42.
Stewart-Hutchinson PJ, Hale CM, Wirtz D, Hodzic D. Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness. Exp Cell Res. 2008;314:1892–905.CrossRefPubMedPubMedCentral
43.
Macaulay IC, Haerty W, Kumar P, Li YI, TX H, Teng MJ, et al. G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. Nat Methods. 2015;12:519–22.CrossRefPubMed
44.
Teye K, Tsuneoka M, Arima N, Koda Y, Nakamura Y, Ueta Y, et al. Increased expression of a Myc target gene Mina53 in human colon cancer. Am J Pathol. 2004;164:205–16.CrossRefPubMedPubMedCentral
45.
González-González M, Fontanillo C, Abad MM, Gutiérrez ML, Mota I, Bengoechea O, et al. Identification of a characteristic copy number alteration profile by high-resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer. Cancer. 2014;120:1948–59.CrossRefPubMed
46.
Hardiman KM, Ulintz PJ, Kuick RD, Hovelson DH, Gates CM, Bhasi A, et al. Intra-tumor genetic heterogeneity in rectal cancer. Lab Investig. 2016;96:4–15.CrossRefPubMed
47.
Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–45.CrossRefPubMed
48.
Bettoni F, Masotti C, Habr-Gama A, Correa BR, Gama-Rodrigues J, Vianna MR, et al. Intratumoral genetic heterogeneity in rectal cancer: are single biopsies representative of the entirety of the tumor? Ann Surg. 2017;265:e4–6.CrossRefPubMed
Metadata
Title
Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer
Authors
Mingshan Liu
Yang Liu
Jiabo Di
Zhe Su
Hong Yang
Beihai Jiang
Zaozao Wang
Meng Zhuang
Fan Bai
Xiangqian Su
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3777-4

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Meta-analysis of gene expression in relapsed childhood B-acute lymphoblastic leukemia

Research article

The enablers, barriers and preferences of accessing radiation therapy facilities in the rural developed world – a systematic review

Research article

Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo

Research article

Outcome and toxicity of radical radiotherapy or concurrent Chemoradiotherapy for elderly cervical cancer women

Research article

Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients

Research article

Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits