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:

Cellular and Molecular Biology

Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases

Abstract

Background

Small bowel adenocarcinoma is a rare disease. The genomic profiling tumours according to clinical characteristics and its impact on the prognosis remains unclear.

Methods

A pooled analysis of clinical data, genomic profiling and MisMatch Repair (MMR) status from three databases was performed.

Results

A total of 188 tumour samples were analysed. A predisposing disease was reported in 22.3%, mainly Lynch syndrome and Crohn’s disease. The tumours were localized in 80.2% and metastatic in 18.8%. The most frequent mutations were KRAS (42.0%) among them 7/79 are G12C, TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%) and ERBB2 (9.6%). Mutation distribution differed according to predisposing disease for TP53, ERBB2, IDH1, FGFR3, FGFR1 and KDR. KRAS and SMAD4 mutations were more frequent in metastatic tumour, whereas ERBB2 mutations were absent in metastatic tumour. For localized tumour, APC mutation was independently associated with a poor overall survival (OS) (p = 0.0254). 31.8% of localized tumours and 11.3% of metastatic tumours were dMMR (29.8% of the entire cohort). A dMMR status was associated with a better OS (HR = 0.61 [0.39–0.96], p = 0.0316).

Conclusions

There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

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

Access options

Buy this article

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

Fig. 1
Fig. 2: Overall survival according to APC mutation.
Fig. 3: Overall survival according to mismatch repair phenotype.

Similar content being viewed by others

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Aparicio T, Pachev A, Laurent-Puig P, Svrcek M. Epidemiology, Risk Factors and Diagnosis of Small Bowel Adenocarcinoma. Cancers. 2022;14:2268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  3. Bouvier AM, Robaszkiewicz M, Jooste V, Cariou M, Drouillard A, Bouvier V, et al. Trends in incidence of small bowel cancer according to histology: a population-based study. J Gastroenterol. 2020;55:181–8.

    Article  CAS  PubMed  Google Scholar 

  4. Legué LM, Bernards N, Gerritse SL, van Oudheusden TR, de Hingh IHJT, Creemers GJM, et al. Trends in incidence, treatment and survival of small bowel adenocarcinomas between 1999 and 2013: a population-based study in The Netherlands. Acta Oncol Stock Swed. 2016;55:1183–9.

    Article  Google Scholar 

  5. Aparicio T, Henriques J, Manfredi S, Tougeron D, Bouché O, Pezet D, et al. Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients. Int J Cancer. 2020;147:967–77.

    Article  CAS  PubMed  Google Scholar 

  6. Haan JC, Buffart TE, Eijk PP, van de Wiel MA, van Wieringen WN, Howdle PD, et al. Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers. Ann Oncol J Eur Soc Med Oncol. 2012;23:367–74.

    Article  CAS  Google Scholar 

  7. Schrock AB, Devoe CE, McWilliams R, Sun J, Aparicio T, Stephens PJ, et al. Genomic Profiling of Small-Bowel Adenocarcinoma. JAMA Oncol. 2017;3:1546–53.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Laforest A, Aparicio T, Zaanan A, Silva FP, Didelot A, Desbeaux A, et al. ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Eur J Cancer Oxf Engl 1990. 2014;50:1740–6.

    CAS  Google Scholar 

  9. Hänninen UA, Katainen R, Tanskanen T, Plaketti RM, Laine R, Hamberg J, et al. Exome-wide somatic mutation characterization of small bowel adenocarcinoma. PLoS Genet. 2018;14:e1007200.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Aparicio T, Svrcek M, Henriques J, Afchain P, Lièvre A, Tougeron D, et al. Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort. Int J Cancer. 2021;148:1731–42.

    Article  CAS  PubMed  Google Scholar 

  11. Adam L, San Lucas FA, Fowler R, Yu Y, Wu W, Liu Y, et al. DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway. Clin Cancer Res J Am Assoc Cancer Res. 2019;25:641–51.

    Article  CAS  Google Scholar 

  12. Casadei-Gardini A, Lonardi S, Smiroldo V, Canale M, Passardi A, Silvestris N, et al. Extensive molecular reclassification: new perspectives in small bowel adenocarcinoma? Med Oncol Northwood Lond Engl. 2021;38:17.

    Article  CAS  Google Scholar 

  13. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol J Am Soc Clin Oncol. 2020;38:1–10.

    Article  CAS  Google Scholar 

  14. Aparicio T, Svrcek M, Zaanan A, Beohou E, Laforest A, Afchain P, et al. Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study. Br J Cancer. 2013;109:3057–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vanoli A, Grillo F, Guerini C, Neri G, Arpa G, Klersy C, et al. Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas. Ann Surg Oncol. 2021;28:1167–77.

    Article  PubMed  Google Scholar 

  16. Jun SY, Kim M, Jin Gu M, Kyung Bae Y, Chang HK, Sun Jung E, et al. Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma. Mod Pathol J U S Can Acad Pathol Inc. 2016;29:402–15.

    CAS  Google Scholar 

  17. Alvi MA, McArt DG, Kelly P, Fuchs MA, Alderdice M, McCabe CM, et al. Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. Oncotarget. 2015;6:20863–74.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pandya K, Overman MJ, Gulhati P. Molecular Landscape of Small Bowel Adenocarcinoma. Cancers. 2022;14:1287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med J Am Coll Med Genet. 2015;17:405–24.

    Google Scholar 

  20. Hammoudi N, Lehmann-Che J, Lambert J, Amoyel M, Maggiori L, Salfati D, et al. Prognosis and molecular characteristics of IBD-associated colorectal cancer: Experience from a French tertiary-care center. Dig Liver Dis J Ital Soc Gastroenterol Ital Assoc Study Liver. 2023;55:1280–7. S1590-8658(23)00225-6

    CAS  Google Scholar 

  21. Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SHI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N. Engl J Med. 2023;388:44–54.

    Article  CAS  PubMed  Google Scholar 

  22. Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, et al. Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer. N. Engl J Med. 2023;388:33–43.

    Article  CAS  PubMed  Google Scholar 

  23. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N. Engl J Med. 2019;381:1632–43.

    Article  CAS  PubMed  Google Scholar 

  24. Yaeger R, Shah MA, Miller VA, Kelsen JR, Wang K, Heins ZJ, et al. Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease. Gastroenterology. 2016;151:278–87.

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Mondaca S, Walch H, Nandakumar S, Chatila WK, Schultz N, Yaeger R. Specific Mutations in APC, but Not Alterations in DNA Damage Response, Associate With Outcomes of Patients With Metastatic Colorectal Cancer. Gastroenterology. 2020;159:1975–8.e4.

    Article  CAS  PubMed  Google Scholar 

  27. Liao X, Li G, McBride R, Houldsworth J, Harpaz N, Polydorides AD. Clinicopathological and Molecular Characterisation of Crohn’s Disease-associated Small Bowel Adenocarcinomas. J Crohns Colitis. 2020;14:287–94.

    Article  PubMed  Google Scholar 

  28. Donahu TF, Bagrodia A, Audenet F, Donoghue MTA, Cha EK, Sfakianos JP, et al. Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome. JCO Precis Oncol [Internet]. 2018 [cité 20 avr 2020];2018. Disponible sur: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404976/

  29. Kondelin J, Salokas K, Saarinen L, Ovaska K, Rauanheimo H, Plaketti RM, et al. Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer. EMBO Mol Med. 2018;10:e8552.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Boyer C, Sefrioui D, Cohen R, Chautard R, Perrier M, Lebrun H, et al. Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability. Dig Liver Dis J Ital Soc Gastroenterol Ital Assoc Study Liver. 2023;55:123–30.

    CAS  Google Scholar 

  31. Coutzac C, Bibeau F, Ben Abdelghani M, Aparicio T, Cohen R, Coquan E, et al. Immunotherapy in MSI/dMMR tumors in the perioperative setting: The IMHOTEP trial. Dig Liver Dis J Ital Soc Gastroenterol Ital Assoc Study Liver. 2022;54:1335–41.

    CAS  Google Scholar 

  32. André T, Tougeron D, Piessen G, de la Fouchardière C, Louvet C, Adenis A, et al. Neoadjuvant Nivolumab Plus Ipilimumab and Adjuvant Nivolumab in Localized Deficient Mismatch Repair/Microsatellite Instability-High Gastric or Esophagogastric Junction Adenocarcinoma: The GERCOR NEONIPIGA Phase II Study. J Clin Oncol J Am Soc Clin Oncol. 2023;41:255–65.

    Article  Google Scholar 

  33. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566–76.

    Article  CAS  PubMed  Google Scholar 

  34. Bennett CM, Coleman HG, Veal PG, Cantwell MM, Lau CCL, Murray LJ. Lifestyle factors and small intestine adenocarcinoma risk: A systematic review and meta-analysis. Cancer Epidemiol. 2015;39:265–73.

    Article  PubMed  Google Scholar 

  35. Ewans J, Aparicio T, Le Malicot K, Nakamura K, Homma Y, Mc Williams R. GLOBAL BALLAD: An International Rare Cancers Initiative trial to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma (IRCI 002). In Chicago: J Clin Oncol; 2016. p. TPS4154.

Download references

Acknowledgements

BIONADEGE and AGEO study were granted by INCa and sponsor by Assistance Publique Hôpitaux de Paris (Délégation à la Recherche Clinique). ARCAD-NADEGE cohort was granted by A.R.C.A.D. and sponsored by GERCOR.

Funding

BIONADEGE was supported by a grant from INCa (Programme Hospitalier de Recherche Translationelle Cancer, PRTK14 N°091) and a grant n° NA 2009 from the A.R.CA.D. foundation. AGEO study was supported by a grant from INCa (Programme Hospitalier de Recherche Clinique, PHRC AOM 09204).

Author information

Authors and Affiliations

Authors

Contributions

Study design: TA, MS, JH, DV and PLP. Data acquisition: TA, MS, AZ, SM, ACG, DT, JMG, DP, ET, GP, PA, CL, MP, TL, VB, FDF, SLD, SC, PLP. Statistical analysis: JH and DV. Manuscript preparation: TA, MS, JH, DV and PLP. Manuscript review: all authors.

Corresponding author

Correspondence to Thomas Aparicio.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

This study was performed in accordance with the Declaration of Helsinki and was authorised by the ethics committee “Ile de France II” No. ID-RCB: 2008-A01058-47 for the French part and by the local Area Vasta Emilia Nord Ethics committee for the Italian part.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aparicio, T., Henriques, J., Svrcek, M. et al. Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases. Br J Cancer 131, 49–62 (2024). https://doi.org/10.1038/s41416-024-02687-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-024-02687-7

Search

Quick links