Taiki Hashimoto1, Daisuke Takayanagi2, Junpei Yonemaru1, Tomoaki Naka1, Kengo Nagashima3, Yasushi Yatabe1,4, Dai Shida5,6, Ryuji Hamamoto7, Sam O Kleeman8, Simon J Leedham9, Timothy Maughan10, Atsuo Takashima11, Kouya Shiraishi2, Shigeki Sekine12,13. 1. Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. 2. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. 3. Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan. 4. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan. 5. Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan. 6. Division of Frontier Surgery, The Institute of Medical Science, Tokyo, Japan. 7. Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan. 8. Cold Spring Harbor Laboratory, New York, NY, USA. 9. Intestinal Stem Cell Biology Lab, Welcome Trust Centre Human Genetics, University of Oxford, Oxford, UK. 10. Department of Oncology, University of Oxford, Oxford, UK. 11. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 12. Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. ssekine@ncc.go.jp. 13. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan. ssekine@ncc.go.jp.
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.
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.
Authors: Jinru Shia; Nikolaus Schultz; Deborah Kuk; Efsevia Vakiani; Sumit Middha; Neil H Segal; Jaclyn F Hechtman; Michael F Berger; Zsofia K Stadler; Martin R Weiser; Jedd D Wolchok; C Richard Boland; Mithat Gönen; David S Klimstra Journal: Mod Pathol Date: 2016-12-16 Impact factor: 7.842
Authors: Felix Dietlein; Donate Weghorn; Amaro Taylor-Weiner; André Richters; Brendan Reardon; David Liu; Eric S Lander; Eliezer M Van Allen; Shamil R Sunyaev Journal: Nat Genet Date: 2020-02-03 Impact factor: 38.330
Authors: Somasekar Seshagiri; Eric W Stawiski; Steffen Durinck; Zora Modrusan; Elaine E Storm; Caitlin B Conboy; Subhra Chaudhuri; Yinghui Guan; Vasantharajan Janakiraman; Bijay S Jaiswal; Joseph Guillory; Connie Ha; Gerrit J P Dijkgraaf; Jeremy Stinson; Florian Gnad; Melanie A Huntley; Jeremiah D Degenhardt; Peter M Haverty; Richard Bourgon; Weiru Wang; Hartmut Koeppen; Robert Gentleman; Timothy K Starr; Zemin Zhang; David A Largaespada; Thomas D Wu; Frederic J de Sauvage Journal: Nature Date: 2012-08-30 Impact factor: 49.962
Authors: Laura S Rozek; Stephanie L Schmit; Joel K Greenson; Lynn P Tomsho; Hedy S Rennert; Gad Rennert; Stephen B Gruber Journal: J Natl Cancer Inst Date: 2016-05-12 Impact factor: 13.506
Authors: Caitlin B Conboy; Germán L Vélez-Reyes; Susan K Rathe; Juan E Abrahante; Nuri A Temiz; Michael B Burns; Reuben S Harris; Timothy K Starr; David A Largaespada Journal: DNA Cell Biol Date: 2020-12-15 Impact factor: 3.311
Authors: Robert N Jorissen; Michael Christie; Dmitri Mouradov; Anuratha Sakthianandeswaren; Shan Li; Christopher Love; Zheng-Zhou Xu; Peter L Molloy; Ian T Jones; Stephen McLaughlin; Robyn L Ward; Nicholas J Hawkins; Andrew R Ruszkiewicz; James Moore; Antony W Burgess; Dana Busam; Qi Zhao; Robert L Strausberg; Lara Lipton; Jayesh Desai; Peter Gibbs; Oliver M Sieber Journal: Br J Cancer Date: 2015-08-25 Impact factor: 7.640