Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

David S. Williams; Dmitri Mouradov; Robert N. Jorissen; Marsali R. Newman; Elham Amini; David K. Nickless; Julie A. Teague; Catherine G. Fang; Michelle Palmieri; Marie J. Parsons; Anuratha Sakthianandeswaren; Shan Li; Robyn L. Ward; Nicholas J. Hawkins; Ian Faragher; Ian T. Jones; Peter Gibbs; Oliver M. Sieber

doi:10.1136/gutjnl-2017-315664

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

David S. Williams, Dmitri Mouradov, Robert N. Jorissen, Marsali R. Newman, Elham Amini, David K. Nickless, Julie A. Teague, Catherine G. Fang, Michelle Palmieri, Marie J. Parsons, Anuratha Sakthianandeswaren, Shan Li, Robyn L. Ward, Nicholas J. Hawkins, Ian Faragher, Ian T. Jones, Peter Gibbs, Oliver M. Sieber

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAF wt/KRAS wt, pMMR/BRAF mut/KRAS wt, pMMR/BRAF wt/KRAS mut) and transcriptomic (CMS 1-4) subtypes. Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

Original language	English
Pages (from-to)	465-474
Journal	Gut
Volume	68
Issue number	3
DOIs	https://doi.org/10.1136/gutjnl-2017-315664
Publication status	Published - 1 Mar 2019
Externally published	Yes

Keywords

colorectal carcinoma
immune response
molecular pathology
tumour markers

ASJC Scopus subject areas

Gastroenterology

Access to Document

10.1136/gutjnl-2017-315664

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Cite this

Williams, D. S., Mouradov, D., Jorissen, R. N., Newman, M. R., Amini, E., Nickless, D. K., Teague, J. A., Fang, C. G., Palmieri, M., Parsons, M. J., Sakthianandeswaren, A., Li, S., Ward, R. L., Hawkins, N. J., Faragher, I., Jones, I. T., Gibbs, P., & Sieber, O. M. (2019). Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. Gut, 68(3), 465-474. https://doi.org/10.1136/gutjnl-2017-315664

Williams, David S. ; Mouradov, Dmitri ; Jorissen, Robert N. ; Newman, Marsali R. ; Amini, Elham ; Nickless, David K. ; Teague, Julie A. ; Fang, Catherine G. ; Palmieri, Michelle ; Parsons, Marie J. ; Sakthianandeswaren, Anuratha ; Li, Shan ; Ward, Robyn L. ; Hawkins, Nicholas J. ; Faragher, Ian ; Jones, Ian T. ; Gibbs, Peter ; Sieber, Oliver M. / Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. In: Gut. 2019 ; Vol. 68, No. 3. pp. 465-474.

@article{3294ec4f2e904ad8bb495fb6a2a4179c,

title = "Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes",

abstract = "Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAF wt/KRAS wt, pMMR/BRAF mut/KRAS wt, pMMR/BRAF wt/KRAS mut) and transcriptomic (CMS 1-4) subtypes. Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.",

keywords = "colorectal carcinoma, immune response, molecular pathology, tumour markers",

author = "Williams, {David S.} and Dmitri Mouradov and Jorissen, {Robert N.} and Newman, {Marsali R.} and Elham Amini and Nickless, {David K.} and Teague, {Julie A.} and Fang, {Catherine G.} and Michelle Palmieri and Parsons, {Marie J.} and Anuratha Sakthianandeswaren and Shan Li and Ward, {Robyn L.} and Hawkins, {Nicholas J.} and Ian Faragher and Jones, {Ian T.} and Peter Gibbs and Sieber, {Oliver M.}",

note = "Funding Information: Funding this work was supported by a cancer australia Project grant (aPP1120882), a cancer council Victoria grant-in-aid (1060964), the Victorian government{\textquoteright}s Operational infrastructure Support Program, a University of Melbourne Department of Pathology career Development award and an austin Medical research Foundation Project grant. OMS is a nHMrc rD. Wright Biomedical Fellow (aPP1062226). MP is supported by a cancer therapeutics crc (ctx) top Up PhD Scholarship and australian government research training Program Scholarship. Funding Information: This work was supported by a Cancer Australia Project Grant (APP1120882), a Cancer Council Victoria Grant-in-Aid (1060964), the Victorian Government's Operational Infrastructure Support Program, a University of Melbourne Department of Pathology Career Development Award and an Austin Medical Research Foundation Project Grant. OMS is a NHMRC RD. Wright Biomedical Fellow (APP1062226).",

year = "2019",

month = mar,

day = "1",

doi = "10.1136/gutjnl-2017-315664",

language = "English",

volume = "68",

pages = "465--474",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "3",

}

Williams, DS, Mouradov, D, Jorissen, RN, Newman, MR, Amini, E, Nickless, DK, Teague, JA, Fang, CG, Palmieri, M, Parsons, MJ, Sakthianandeswaren, A, Li, S, Ward, RL, Hawkins, NJ, Faragher, I, Jones, IT, Gibbs, P & Sieber, OM 2019, 'Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes', Gut, vol. 68, no. 3, pp. 465-474. https://doi.org/10.1136/gutjnl-2017-315664

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. / Williams, David S.; Mouradov, Dmitri; Jorissen, Robert N.; Newman, Marsali R.; Amini, Elham; Nickless, David K.; Teague, Julie A.; Fang, Catherine G.; Palmieri, Michelle; Parsons, Marie J.; Sakthianandeswaren, Anuratha; Li, Shan; Ward, Robyn L.; Hawkins, Nicholas J.; Faragher, Ian; Jones, Ian T.; Gibbs, Peter; Sieber, Oliver M.

In: Gut, Vol. 68, No. 3, 01.03.2019, p. 465-474.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

AU - Williams, David S.

AU - Mouradov, Dmitri

AU - Jorissen, Robert N.

AU - Newman, Marsali R.

AU - Amini, Elham

AU - Nickless, David K.

AU - Teague, Julie A.

AU - Fang, Catherine G.

AU - Palmieri, Michelle

AU - Parsons, Marie J.

AU - Sakthianandeswaren, Anuratha

AU - Li, Shan

AU - Ward, Robyn L.

AU - Hawkins, Nicholas J.

AU - Faragher, Ian

AU - Jones, Ian T.

AU - Gibbs, Peter

AU - Sieber, Oliver M.

N1 - Funding Information: Funding this work was supported by a cancer australia Project grant (aPP1120882), a cancer council Victoria grant-in-aid (1060964), the Victorian government’s Operational infrastructure Support Program, a University of Melbourne Department of Pathology career Development award and an austin Medical research Foundation Project grant. OMS is a nHMrc rD. Wright Biomedical Fellow (aPP1062226). MP is supported by a cancer therapeutics crc (ctx) top Up PhD Scholarship and australian government research training Program Scholarship. Funding Information: This work was supported by a Cancer Australia Project Grant (APP1120882), a Cancer Council Victoria Grant-in-Aid (1060964), the Victorian Government's Operational Infrastructure Support Program, a University of Melbourne Department of Pathology Career Development Award and an Austin Medical Research Foundation Project Grant. OMS is a NHMRC RD. Wright Biomedical Fellow (APP1062226).

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAF wt/KRAS wt, pMMR/BRAF mut/KRAS wt, pMMR/BRAF wt/KRAS mut) and transcriptomic (CMS 1-4) subtypes. Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

AB - Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAF wt/KRAS wt, pMMR/BRAF mut/KRAS wt, pMMR/BRAF wt/KRAS mut) and transcriptomic (CMS 1-4) subtypes. Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

KW - colorectal carcinoma

KW - immune response

KW - molecular pathology

KW - tumour markers

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U2 - 10.1136/gutjnl-2017-315664

DO - 10.1136/gutjnl-2017-315664

M3 - Article

C2 - 29382774

AN - SCOPUS:85047961532

VL - 68

SP - 465

EP - 474

JO - Gut

JF - Gut

SN - 0017-5749

IS - 3

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