Rectal cancer sub-clones respond differentially to neoadjuvant therapy.
Journal: 2019/September - Neoplasia
ISSN: 1476-5586
Abstract:
Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. Genomic data were analyzed using PyClone to identify sub-clonal tumor population following nCRT. Alterations that persisted or were enriched in the post-treatment tumor specimen following nCRT were defined for each patient. Thirty-two samples were obtained from ten patients. PyClone identified 2 to 10 genetic sub-clones per tumor. Substantial changes in the proportions of individual sub-clones in pre- versus post-treatment tumor material were found in all patients. Resistant sub-clones recurrently contained mutations in TP53, APC, ABCA13, MUC16, and THSD4. Recurrent copy number variation was observed across multiple chromosome regions after nCRT. Pathway analysis including variant alleles and copy number changes associated with resistant sub-clones revealed significantly altered pathways, especially those linked to the APC and TP53 genes, which were the two most frequently mutated genes. Intra-tumoral heterogeneity is evident in pre-treatment rectal cancer. Following treatment, sub-clonal populations are selectively modified and enrichment of a subset of pre-treatment sub-clones is seen. Further studies are needed to define recurrent alterations at diagnosis that may contribute to resistance to nCRT.
Relations:
Content
Citations
(3)
References
(39)
Genes
(4)
Processes
(5)
Affiliates
(2)
Similar articles
Articles by the same authors
Discussion board
Neoplasia 21(10): 1051-1062

Rectal cancer sub-clones respond differentially to neoadjuvant therapy<sup><sup><a href="#d31e1222" rid="d31e1222" class=" fn">☆</a></sup></sup>

Department of Surgery, Michigan Medicine, Ann Arbor, MI 48109
Bioinformatics Core, Michigan Medicine, Ann Arbor, MI 48109
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109
Department of Pathology, Michigan Medicine, Ann Arbor, MI 48109
Division of Colorectal Surgery, Department of Surgery, Michigan Medicine, Ann Arbor, MI 48109
Division of Gastrointestinal Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109
Lynn M Frydrych: ude.hcimu.dem@cyrdyrfl; Peter Ulintz: ude.hcimu@ztnilup; Armand Bankhead: ude.hcimu.dem@daehknab; Christopher Sifuentes: ude.hcimu.dem@neufisjc; Joel Greenson: ude.hcimu.dem@dmgkjcaf; Lillias Maguire: ude.hcimu.dem@leriugam; Regina Irwin: ude.hcimu.dem@erniwri; Eric R. Fearon: ude.hcimu.dem@noraef; Karin M Hardiman: ude.cmbau@namidrahk
Address all correspondence to: Karin M Hardiman, Department of Surgery, 428 Kracke Building, 1922 7 Ave S, Birmingham, AL 35294. ude.cmbau@namidrahk
Received 2019 May 23; Revised 2019 Aug 13; Accepted 2019 Aug 15.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinical Stage is determined by endorectal ultrasound (u) or MRI (m) and is according to AJCC, 8th Edition; Gy = Gray; APR = Abdominoperineal resection of the rectum; LAR = Low anterior resection of the rectum; yp indicates pathology stage after neo-adjuvant treatment.

Bold, Resistant alteration.

Click here to view.Supplemental Table 1Click here to view.Supplemental Table 2Click here to view.Supplemental Table 3Click here to view.(15K, xlsx)Click here to view.Supplemental Figure 1Click here to view.Supplemental Figure 3

Footnotes

Conflicts of Interest: None

Footnotes

References

  • 1. Brenner H, Kloor M, Pox CPColorectal cancer. Lancet. 2014;383:1490–1502.[PubMed][Google Scholar]
  • 2. Siegel R, Naishadham D, Jemal ACancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.[PubMed][Google Scholar]
  • 3. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJPreoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575–582.[PubMed][Google Scholar]
  • 4. Habr-Gama A, de Souza PM, Ribeiro U, Jr., Nadalin W, Gansl R, Sousa AH, Jr., Campos FG, Gama-Rodrigues JLow rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon Rectum. 1998;41:1087–1096.[PubMed][Google Scholar]
  • 5. Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DAA pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum. 2003;46:298–304.[PubMed][Google Scholar]
  • 6. Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM, Ng K, Ma J, Wienholds E, Dunant CVariable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339:543–548.[PubMed][Google Scholar]
  • 7. Hardiman KM, Ulintz PJ, Kuick RD, Hovelson DH, Gates CM, Bhasi A, Rodrigues Grant A, Liu J, Cani AK, Greenson JKIntra-tumor genetic heterogeneity in rectal cancer. Lab Investig. 2016;96:4–15.[Google Scholar]
  • 8. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata DA Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47:209–216.[Google Scholar]
  • 9. Ulintz PJ, Greenson JK, Wu R, Fearon ER, Hardiman KMLymph Node Metastases in Colon Cancer Are Polyclonal. Clin Cancer Res. 2018;24:2214–2224.[Google Scholar]
  • 10. Wheeler JM, Dodds E, Warren BF, Cunningham C, George BD, Jones AC, Mortensen NJPreoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal cancer regression grade. Dis Colon Rectum. 2004;47:2025–2031.[PubMed][Google Scholar]
  • 11. Frank DNBARCRAWL and BARTAB: software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing. BMC Bioinformatics. 2009;10:362.[Google Scholar]
  • 12. Li H, Durbin RFast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760.[Google Scholar]
  • 13. Hagemann IS, Devarakonda S, Lockwood CM, Spencer DH, Guebert K, Bredemeyer AJ, Al-Kateb H, Nguyen TT, Duncavage EJ, Cottrell CEClinical next-generation sequencing in patients with non-small cell lung cancer. Cancer. 2015;121:631–639.[PubMed][Google Scholar]
  • 14. Mayrhofer M, DiLorenzo S, Isaksson APatchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue. Genome Biol. 2013;14:R24.[Google Scholar]
  • 15. McPherson A, Roth A, Laks E, Masud T, Bashashati A, Zhang AW, Ha G, Biele J, Yap D, Wan ADivergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat Genet. 2016;48:758–767.[PubMed][Google Scholar]
  • 16. Roth A, Khattra J, Yap D, Wan A, Laks E, Biele J, Ha G, Aparicio S, Bouchard-Cote A, Shah SPPyClone: statistical inference of clonal population structure in cancer. Nat Methods. 2014;11:396–398.[Google Scholar]
  • 17. Lamy P, Nordentoft I, Birkenkamp-Demtroder K, Thomsen MB, Villesen P, Vang S, Hedegaard J, Borre M, Jensen JB, Hoyer SPaired Exome Analysis Reveals Clonal Evolution and Potential Therapeutic Targets in Urothelial Carcinoma. Cancer Res. 2016;76:5894–5906.[PubMed][Google Scholar]
  • 18. Findlay JM, Castro-Giner F, Makino S, Rayner E, Kartsonaki C, Cross W, Kovac M, Ulahannan D, Palles C, Gillies RSDifferential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy. Nat Commun. 2016;7:11111.[Google Scholar]
  • 19. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, Rudolph JE, Yaeger R, Soumerai T, Nissan MHOncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017;2017[Google Scholar]
  • 20. Leiserson MD, Vandin F, Wu HT, Dobson JR, Eldridge JV, Thomas JL, Papoutsaki A, Kim Y, Niu B, McLellan MPan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. Nat Genet. 2015;47:106–114.[Google Scholar]
  • 21. Jiao X, Sherman BT, Huang da W, Stephens R, Baseler MW, Lane HC, Lempicki RADAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012;28:1805–1806.[Google Scholar]
  • 22. Edgar R, Domrachev M, Lash AEGene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–210.[Google Scholar]
  • 23. Xie T, G DA, Lamb JR, Martin E, Wang K, Tejpar S, Delorenzi M, Bosman FT, Roth AD, Yan PA comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations. PLoS One. 2012;7[Google Scholar]
  • 24. Cancer Genome Atlas N Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337.
  • 25. Sakai K, Kazama S, Nagai Y, Murono K, Tanaka T, Ishihara S, Sunami E, Tomida S, Nishio K, Watanabe TChemoradiation provides a physiological selective pressure that increases the expansion of aberrant TP53 tumor variants in residual rectal cancerous regions. Oncotarget. 2014;5:9641–9649.[Google Scholar]
  • 26. Chow OS, Kuk D, Keskin M, Smith JJ, Camacho N, Pelossof R, Chen CT, Chen Z, Avila K, Weiser MRKRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy. Ann Surg Oncol. 2016;23:2548–2555.[Google Scholar]
  • 27. Zhang T, Ma Z, Liu L, Sun J, Tang H, Zhang B, Zou Y, Li HDDX39 promotes hepatocellular carcinoma growth and metastasis through activating Wnt/beta-catenin pathway. Cell Death Dis. 2018;9:675.[Google Scholar]
  • 28. Li Y, Li L, Chen M, Yu X, Gu Z, Qiu H, Qin G, Long Q, Fu X, Liu TMAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Mol Oncol. 2018;12:391–405.[Google Scholar]
  • 29. Roderick HL, Cook SJCa2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer. 2008;8:361–375.[PubMed][Google Scholar]
  • 30. Prevarskaya N, Skryma R, Shuba YCalcium in tumour metastasis: new roles for known actors. Nat Rev Cancer. 2011;11:609–618.[PubMed][Google Scholar]
  • 31. Fiorio Pla A, Avanzato D, Munaron L, Ambudkar IS. Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets. Am J Physiol Cell Physiol. 2012;302:C9–15.[PubMed]
  • 32. Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi MGenomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016;17:1206.[Google Scholar]
  • 33. Emons G, Spitzner M, Reineke S, Moller J, Auslander N, Kramer F, Hu Y, Beissbarth T, Wolff HA, Rave-Frank MChemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/beta-catenin Signaling. Mol Cancer Res. 2017;15:1481–1490.[Google Scholar]
  • 34. Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R, Liska V, Pitule P, Novak P, Bruha J, Vycital O, Holubec L, Treska VThe role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis. 2012;27:187–196.[PubMed][Google Scholar]
  • 35. Araujo TM, Seabra AD, Lima EM, Assumpcao PP, Montenegro RC, Demachki S, Burbano RM, Khayat ASRecurrent amplification of RTEL1 and ABCA13 and its synergistic effect associated with clinicopathological data of gastric adenocarcinoma. Mol Cytogenet. 2016;9:52.[Google Scholar]
  • 36. Nymoen DA, Holth A, Hetland Falkenthal TE, Trope CG, Davidson BCIAPIN1 and ABCA13 are markers of poor survival in metastatic ovarian serous carcinoma. Mol Cancer. 2015;14:44.[Google Scholar]
  • 37. Chang SJ, Ge XS, Xu ZY, Qi XW, Chen XPLower serum CA125 level, negative vascular invasion, and wild BRAF were strongly associated with better 2-year disease-free survival in patients with stage III colorectal cancer who received adjuvant chemotherapy. Cancer Biomark. 2018;22:161–168.[PubMed][Google Scholar]
  • 38. Ma D, Yang J, Wang Y, Huang X, Du G, Zhou LWhole exome sequencing identified genetic variations in Chinese hemangioblastoma patients. Am J Med Genet A. 2017;173:2605–2613.[Google Scholar]
  • 39. Ma J, Hou X, Li M, Ren H, Fang S, Wang X, He CGenome-wide methylation profiling reveals new biomarkers for prognosis prediction of glioblastoma. J Cancer Res Ther. 2015;11(Suppl 2):C212–C215.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.