Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical Studies

Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer

British Journal of Cancer volume 127, pages 1043–1050 (2022)Cite this article

Subjects

Abstract

Background

RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear.

Methods

We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription–PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES).

Results

Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10−7). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies.

Conclusion

RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Histology of RSPO fusion-positive colorectal cancer.
Fig. 2: Summary of whole-exome sequencing analysis.
Fig. 3: Kaplan–Meier curves, stratified by RSPO fusion status.

Similar content being viewed by others

Data availability

Nucleotide sequence data reported are available in the DDBJ database under the accession number JGAS000538.

References

  1. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  Google Scholar 

  2. Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet. 2014;46:1264–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A, Sanchez-Vega F, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125–36.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kleeman SO, Leedham SJ. Not all Wnt activation is equal: ligand-dependent versus ligand-independent Wnt activation in colorectal cancer. Cancers. 2020;12:3355.

    Article  CAS  PubMed Central  Google Scholar 

  5. Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476:293–7.

    Article  PubMed  Google Scholar 

  7. Storm EE, Durinck S, de Sousa e Melo F, Tremayne J, Kljavin N, Tan C, et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature. 2016;529:97–100.

    Article  CAS  PubMed  Google Scholar 

  8. Fischer MM, Yeung VP, Cattaruzza F, Hussein R, Yen WC, Murriel C, et al. RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations. Sci Rep. 2017;7:15270.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35:2197–207.

    Article  CAS  PubMed  Google Scholar 

  10. Li C, Cao J, Zhang N, Tu M, Xu F, Wei S, et al. Identification of RSPO2 fusion mutations and target therapy using a porcupine inhibitor. Sci Rep. 2018;8:14244.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Picco G, Petti C, Centonze A, Torchiaro E, Crisafulli G, Novara L, et al. Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions. EMBO Mol Med. 2017;9:293–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shinmura K, Kahyo T, Kato H, Igarashi H, Matsuura S, Nakamura S, et al. RSPO fusion transcripts in colorectal cancer in Japanese population. Mol Biol Rep. 2014;41:5375–84.

    Article  CAS  PubMed  Google Scholar 

  13. Kloosterman WP, Coebergh van den Braak RRJ, Pieterse M, van Roosmalen MJ, Sieuwerts AM, Stangl C, et al. A systematic analysis of oncogenic gene fusions in primary colon cancer. Cancer Res. 2017;77:3814–22.

    Article  CAS  PubMed  Google Scholar 

  14. Mizuguchi Y, Sakamoto T, Hashimoto T, Tsukamoto S, Iwasa S, Saito Y, et al. Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma. Virchows Arch. 2019;475:659–63.

    Article  CAS  PubMed  Google Scholar 

  15. Kleeman SO, Koelzer VH, Jones HJ, Vazquez EG, Davis H, East JE, et al. Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification. Gut. 2020;69:1092–103.

    Article  CAS  PubMed  Google Scholar 

  16. Yan HHN, Siu HC, Ho SL, Yue SSK, Gao Y, Tsui WY, et al. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles. Gut. 2020;69:2165–79.

    Article  CAS  PubMed  Google Scholar 

  17. Conboy CB, Velez-Reyes GL, Rathe SK, Abrahante JE, Temiz NA, Burns MB, et al. R-Spondins 2 and 3 are overexpressed in a subset of human colon and breast cancers. DNA Cell Biol. 2021;40:70–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sekine S, Ogawa R, Hashimoto T, Motohiro K, Yoshida H, Taniguchi H, et al. Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas. Histopathology. 2017;71:601–9.

    Article  PubMed  Google Scholar 

  19. Hashimoto T, Ogawa R, Yoshida H, Taniguchi H, Kojima M, Saito Y, et al. EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma. Histopathology. 2019;75:266–73.

    Article  PubMed  Google Scholar 

  20. Nagtegaal IDAM, Salto-Tellez M. Colorectal adenocarcinoma. In: WHO Classification of Tumours Editorial Board (ed). WHO classification of tumours digestive system tumors, 5th edn. Lyon, France: IARC Press; 2019. pp. 181–7.

  21. Rozek LS, Schmit SL, Greenson JK, Tomsho LP, Rennert HS, Rennert G, et al. Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst. 2016;108:djw027.

  22. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dietlein F, Weghorn D, Taylor-Weiner A, Richters A, Reardon B, Liu D, et al. Identification of cancer driver genes based on nucleotide context. Nat Genet. 2020;52:208–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–92.

    Article  CAS  PubMed  Google Scholar 

  25. Yonemaru J, Hashimoto T, Takayanagi D, Naka T, Yatabe Y, Kanemitsu Y, et al. NTRK fusion-positive colorectal cancer in Japanese population. Pathol Int. 2021;71:355–9.

    Article  CAS  PubMed  Google Scholar 

  26. Yokota T, Saito Y, Takamaru H, Sekine S, Nakajima T, Yamada M, et al. Spontaneous regression of mismatch repair-deficient colon cancer: a case series. Clin Gastroenterol Hepatol. 2021;19:1720–2.e3.

    Article  PubMed  Google Scholar 

  27. Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 2018;8:730–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, et al. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology. 1986;10:437–59.

    Article  CAS  PubMed  Google Scholar 

  29. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, et al. Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563–70.

    Article  PubMed  Google Scholar 

  30. Gonzalez RS, Cates JMM, Washington K. Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component. Histopathology. 2019;74:406–14.

    Article  PubMed  Google Scholar 

  31. Huang L, Luo S, Zhang X, Cai Y, Xue F, Hu H, et al. Distinct genomic landscape of colorectal mucinous carcinoma determined via comprehensive genomic profiling: steps to a new treatment strategy. Front Oncol. 2021;11:603564.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Shia J, Ellis NA, Paty PB, Nash GM, Qin J, Offit K, et al. Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer. Am J Surg Pathol. 2003;27:1407–17.

    Article  PubMed  Google Scholar 

  33. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rimbert J, Tachon G, Junca A, Villalva C, Karayan-Tapon L, Tougeron D. Association between clinicopathological characteristics and RAS mutation in colorectal cancer. Mod Pathol. 2018;31:517–26.

    Article  CAS  PubMed  Google Scholar 

  35. Shia J, Schultz N, Kuk D, Vakiani E, Middha S, Segal NH, et al. Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations: clinical and biological implications. Mod Pathol. 2017;30:599–609.

    Article  CAS  PubMed  Google Scholar 

  36. Stachler MD, Rinehart E, Lindeman N, Odze R, Srivastava A. Novel molecular insights from routine genotyping of colorectal carcinomas. Hum Pathol. 2015;46:507–13.

    Article  CAS  PubMed  Google Scholar 

  37. Pai RK, Jayachandran P, Koong AC, Chang DT, Kwok S, Ma L, et al. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol. 2012;36:744–52.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sekine S, Yamashita S, Tanabe T, Hashimoto T, Yoshida H, Taniguchi H, et al. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. J Pathol. 2016;239:133–8.

    Article  CAS  PubMed  Google Scholar 

  39. Sekine S, Yamashita S, Yamada M, Hashimoto T, Ogawa R, Yoshida H, et al. Clinicopathological and molecular correlations in traditional serrated adenoma. J Gastroenterol. 2020;55:418–27.

    Article  CAS  PubMed  Google Scholar 

  40. Jorissen RN, Christie M, Mouradov D, Sakthianandeswaren A, Li S, Love C, et al. Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer. Br J Cancer. 2015;113:979–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang C, Ouyang C, Cho M, Ji J, Sandhu J, Goel A, et al. Wild-type APC is associated with poor survival in metastatic microsatellite stable colorectal cancer. Oncologist. 2021;26:208–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Reiko Ogawa, Ms. Sachiko Miura, Ms. Toshiko Sakaguchi and Ms. Chizu Kina for their skilful technical assistance. We also thank Dr. Andrew Blake for help in data preparation. Part of the data used in the preparation of this manuscript were obtained and analysed from the datasets available through the MRC and CRUK funded S:CORT consortium.

Funding

This study was supported by Kurozumi Medical Foundation and JSPS KAKENHI Grant number 20K07382.

Author information

Authors and Affiliations

  1. Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan

    Taiki Hashimoto, Junpei Yonemaru, Tomoaki Naka, Yasushi Yatabe & Shigeki Sekine

  2. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

    Daisuke Takayanagi & Kouya Shiraishi

  3. Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan

    Kengo Nagashima

  4. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Yasushi Yatabe & Shigeki Sekine

  5. Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan

    Dai Shida

  6. Division of Frontier Surgery, The Institute of Medical Science, Tokyo, Japan

    Dai Shida

  7. Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan

    Ryuji Hamamoto

  8. Cold Spring Harbor Laboratory, New York, NY, USA

    Sam O. Kleeman

  9. Intestinal Stem Cell Biology Lab, Welcome Trust Centre Human Genetics, University of Oxford, Oxford, UK

    Simon J. Leedham

  10. Department of Oncology, University of Oxford, Oxford, UK

    Timothy Maughan

  11. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Atsuo Takashima

Authors
  1. Taiki Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daisuke Takayanagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junpei Yonemaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoaki Naka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kengo Nagashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasushi Yatabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dai Shida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryuji Hamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sam O. Kleeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Simon J. Leedham
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Timothy Maughan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Atsuo Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kouya Shiraishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shigeki Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TH, DT, KS and SS carried out experiments and analysed data. TH, JY, TN, YY and SS performed histological analyses. KN conducted the statistical analysis. TH and SS wrote the manuscript. DS, SK, SL, TM and AT provided clinicopathological and mutation data. RH reviewed the paper. All authors provided critical revisions of the final manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shigeki Sekine.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the National Cancer Center Tokyo, Japan. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashimoto, T., Takayanagi, D., Yonemaru, J. et al. Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer. Br J Cancer 127, 1043–1050 (2022). https://doi.org/10.1038/s41416-022-01880-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01880-w

This article is cited by

Search

Advanced search

Quick links