SMAD4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance Journal Article
| Authors: | Wasserman, I.; Lee, L. H.; Ogino, S.; Marco, M. R.; Wu, C.; Chen, X.; Datta, J.; Sadot, E.; Szeglin, B.; Guillem, J. G.; Paty, P. B.; Weiser, M. R.; Nash, G. M.; Saltz, L.; Barlas, A.; Manova-Todorova, K.; Uppada, S. P. B.; Elghouayel, A. E.; Ntiamoah, P.; Glickman, J. N.; Hamada, T.; Kosumi, K.; Inamura, K.; Chan, A. T.; Nishihara, R.; Cercek, A.; Ganesh, K.; Kemeny, N. E.; Dhawan, P.; Yaeger, R.; Sawyers, C. L.; Garcia-Aguilar, J.; Giannakis, M.; Shia, J.; Smith, J. J. |
| Article Title: | SMAD4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance |
| Abstract: | PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer. ©2018 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 6 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-03-15 |
| Start Page: | 1948 |
| End Page: | 1956 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-1726 |
| PUBMED: | 30587545 |
| PROVIDER: | scopus |
| PMCID: | PMC6421131 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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