Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy

A. Collura, A. Lagrange, M. Svrcek, L. Marisa, O. Buhard, A. Guilloux, K. Wanherdrick, C. Dorard, A. Taieb, A. Saget, M. Loh, R. Soong, Nikolajs Zeps, Cameron Platell, A. Mews, Barry Iacopetta, A. De Thonel, R.G. Seigneuric, G. Marcion, C. Chapusot & 18 others C. Lepage, A.M. Bouvier, M.P. Gaub, G.A. Milano, J. Selves, P. Senet, P. Delarue, H. Arzouk, C. Lacoste, A. Coquelle, L. Bengrine-Lefèvre, C. Tournigand, J.H. Lefèvre, Y. Parc, D.S.F. Biard, J.F. Fléjou, C. Garrido, A. Duval

Research output: Contribution to journalArticle

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Abstract

Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17. Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P =.03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). Conclusions About 25% of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA. © 2014 by the AGA Institute.
Original languageEnglish
Pages (from-to)401-411
JournalGastroenterology
Volume146
Issue number2
DOIs
Publication statusPublished - 2014

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Microsatellite Instability
Fluorouracil
Colorectal Neoplasms
Drug Therapy
oxaliplatin
Neoplasms
HSP110 Heat-Shock Proteins
Introns
Surface Plasmon Resonance
Adjuvant Chemotherapy
Exons
Multivariate Analysis
Confidence Intervals
Recurrence
Polymerase Chain Reaction
Survival
DNA

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Collura, A. ; Lagrange, A. ; Svrcek, M. ; Marisa, L. ; Buhard, O. ; Guilloux, A. ; Wanherdrick, K. ; Dorard, C. ; Taieb, A. ; Saget, A. ; Loh, M. ; Soong, R. ; Zeps, Nikolajs ; Platell, Cameron ; Mews, A. ; Iacopetta, Barry ; De Thonel, A. ; Seigneuric, R.G. ; Marcion, G. ; Chapusot, C. ; Lepage, C. ; Bouvier, A.M. ; Gaub, M.P. ; Milano, G.A. ; Selves, J. ; Senet, P. ; Delarue, P. ; Arzouk, H. ; Lacoste, C. ; Coquelle, A. ; Bengrine-Lefèvre, L. ; Tournigand, C. ; Lefèvre, J.H. ; Parc, Y. ; Biard, D.S.F. ; Fléjou, J.F. ; Garrido, C. ; Duval, A. / Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy. In: Gastroenterology. 2014 ; Vol. 146, No. 2. pp. 401-411.
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title = "Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy",
abstract = "Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17. Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4{\%}) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6{\%}) in multivariate analysis (hazard ratio, 0.16; 95{\%} confidence interval, 0.012-0.8; P =.03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). Conclusions About 25{\%} of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA. {\circledC} 2014 by the AGA Institute.",
author = "A. Collura and A. Lagrange and M. Svrcek and L. Marisa and O. Buhard and A. Guilloux and K. Wanherdrick and C. Dorard and A. Taieb and A. Saget and M. Loh and R. Soong and Nikolajs Zeps and Cameron Platell and A. Mews and Barry Iacopetta and {De Thonel}, A. and R.G. Seigneuric and G. Marcion and C. Chapusot and C. Lepage and A.M. Bouvier and M.P. Gaub and G.A. Milano and J. Selves and P. Senet and P. Delarue and H. Arzouk and C. Lacoste and A. Coquelle and L. Bengrine-Lef{\`e}vre and C. Tournigand and J.H. Lef{\`e}vre and Y. Parc and D.S.F. Biard and J.F. Fl{\'e}jou and C. Garrido and A. Duval",
year = "2014",
doi = "10.1053/j.gastro.2013.10.054",
language = "English",
volume = "146",
pages = "401--411",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Elsevier BV",
number = "2",

}

Collura, A, Lagrange, A, Svrcek, M, Marisa, L, Buhard, O, Guilloux, A, Wanherdrick, K, Dorard, C, Taieb, A, Saget, A, Loh, M, Soong, R, Zeps, N, Platell, C, Mews, A, Iacopetta, B, De Thonel, A, Seigneuric, RG, Marcion, G, Chapusot, C, Lepage, C, Bouvier, AM, Gaub, MP, Milano, GA, Selves, J, Senet, P, Delarue, P, Arzouk, H, Lacoste, C, Coquelle, A, Bengrine-Lefèvre, L, Tournigand, C, Lefèvre, JH, Parc, Y, Biard, DSF, Fléjou, JF, Garrido, C & Duval, A 2014, 'Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy' Gastroenterology, vol. 146, no. 2, pp. 401-411. https://doi.org/10.1053/j.gastro.2013.10.054

Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy. / Collura, A.; Lagrange, A.; Svrcek, M.; Marisa, L.; Buhard, O.; Guilloux, A.; Wanherdrick, K.; Dorard, C.; Taieb, A.; Saget, A.; Loh, M.; Soong, R.; Zeps, Nikolajs; Platell, Cameron; Mews, A.; Iacopetta, Barry; De Thonel, A.; Seigneuric, R.G.; Marcion, G.; Chapusot, C.; Lepage, C.; Bouvier, A.M.; Gaub, M.P.; Milano, G.A.; Selves, J.; Senet, P.; Delarue, P.; Arzouk, H.; Lacoste, C.; Coquelle, A.; Bengrine-Lefèvre, L.; Tournigand, C.; Lefèvre, J.H.; Parc, Y.; Biard, D.S.F.; Fléjou, J.F.; Garrido, C.; Duval, A.

In: Gastroenterology, Vol. 146, No. 2, 2014, p. 401-411.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy

AU - Collura, A.

AU - Lagrange, A.

AU - Svrcek, M.

AU - Marisa, L.

AU - Buhard, O.

AU - Guilloux, A.

AU - Wanherdrick, K.

AU - Dorard, C.

AU - Taieb, A.

AU - Saget, A.

AU - Loh, M.

AU - Soong, R.

AU - Zeps, Nikolajs

AU - Platell, Cameron

AU - Mews, A.

AU - Iacopetta, Barry

AU - De Thonel, A.

AU - Seigneuric, R.G.

AU - Marcion, G.

AU - Chapusot, C.

AU - Lepage, C.

AU - Bouvier, A.M.

AU - Gaub, M.P.

AU - Milano, G.A.

AU - Selves, J.

AU - Senet, P.

AU - Delarue, P.

AU - Arzouk, H.

AU - Lacoste, C.

AU - Coquelle, A.

AU - Bengrine-Lefèvre, L.

AU - Tournigand, C.

AU - Lefèvre, J.H.

AU - Parc, Y.

AU - Biard, D.S.F.

AU - Fléjou, J.F.

AU - Garrido, C.

AU - Duval, A.

PY - 2014

Y1 - 2014

N2 - Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17. Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P =.03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). Conclusions About 25% of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA. © 2014 by the AGA Institute.

AB - Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17. Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P =.03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). Conclusions About 25% of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA. © 2014 by the AGA Institute.

U2 - 10.1053/j.gastro.2013.10.054

DO - 10.1053/j.gastro.2013.10.054

M3 - Article

VL - 146

SP - 401

EP - 411

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -