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MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

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MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes. / Fraune, Christoph; Burandt, Eike; Simon, Ronald; Hube-Magg, Claudia; Makrypidi-Fraune, Georgia; Kluth, Martina; Büscheck, Franziska; Höflmayer, Doris; Blessin, Niclas Ch; Mandelkow, Tim; Li, Wenchao; Perez, Daniel; Izbicki, Jakob R; Wilczak, Waldemar; Sauter, Guido; Schrader, Jörg; Neipp, Michael; Mofid, Hamid; Daniels, Thies; Isbert, Christoph; Clauditz, Till S; Steurer, Stefan.

In: ANN SURG ONCOL, Vol. 27, No. 10, 10.2020, p. 3997-4006.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Fraune, C, Burandt, E, Simon, R, Hube-Magg, C, Makrypidi-Fraune, G, Kluth, M, Büscheck, F, Höflmayer, D, Blessin, NC, Mandelkow, T, Li, W, Perez, D, Izbicki, JR, Wilczak, W, Sauter, G, Schrader, J, Neipp, M, Mofid, H, Daniels, T, Isbert, C, Clauditz, TS & Steurer, S 2020, 'MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes', ANN SURG ONCOL, vol. 27, no. 10, pp. 3997-4006. https://doi.org/10.1245/s10434-020-08209-y

APA

Fraune, C., Burandt, E., Simon, R., Hube-Magg, C., Makrypidi-Fraune, G., Kluth, M., Büscheck, F., Höflmayer, D., Blessin, N. C., Mandelkow, T., Li, W., Perez, D., Izbicki, J. R., Wilczak, W., Sauter, G., Schrader, J., Neipp, M., Mofid, H., Daniels, T., ... Steurer, S. (2020). MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes. ANN SURG ONCOL, 27(10), 3997-4006. https://doi.org/10.1245/s10434-020-08209-y

Vancouver

Fraune C, Burandt E, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M et al. MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes. ANN SURG ONCOL. 2020 Oct;27(10):3997-4006. https://doi.org/10.1245/s10434-020-08209-y

Bibtex

@article{ee66158640b244258a51ffad525a627e,
title = "MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes",
abstract = "BACKGROUND: Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking.METHODS: To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.RESULTS: In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response.CONCLUSIONS: Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.",
author = "Christoph Fraune and Eike Burandt and Ronald Simon and Claudia Hube-Magg and Georgia Makrypidi-Fraune and Martina Kluth and Franziska B{\"u}scheck and Doris H{\"o}flmayer and Blessin, {Niclas Ch} and Tim Mandelkow and Wenchao Li and Daniel Perez and Izbicki, {Jakob R} and Waldemar Wilczak and Guido Sauter and J{\"o}rg Schrader and Michael Neipp and Hamid Mofid and Thies Daniels and Christoph Isbert and Clauditz, {Till S} and Stefan Steurer",
year = "2020",
month = oct,
doi = "10.1245/s10434-020-08209-y",
language = "English",
volume = "27",
pages = "3997--4006",
journal = "ANN SURG ONCOL",
issn = "1068-9265",
publisher = "Springer New York",
number = "10",

}

RIS

TY - JOUR

T1 - MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

AU - Fraune, Christoph

AU - Burandt, Eike

AU - Simon, Ronald

AU - Hube-Magg, Claudia

AU - Makrypidi-Fraune, Georgia

AU - Kluth, Martina

AU - Büscheck, Franziska

AU - Höflmayer, Doris

AU - Blessin, Niclas Ch

AU - Mandelkow, Tim

AU - Li, Wenchao

AU - Perez, Daniel

AU - Izbicki, Jakob R

AU - Wilczak, Waldemar

AU - Sauter, Guido

AU - Schrader, Jörg

AU - Neipp, Michael

AU - Mofid, Hamid

AU - Daniels, Thies

AU - Isbert, Christoph

AU - Clauditz, Till S

AU - Steurer, Stefan

PY - 2020/10

Y1 - 2020/10

N2 - BACKGROUND: Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking.METHODS: To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.RESULTS: In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response.CONCLUSIONS: Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.

AB - BACKGROUND: Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking.METHODS: To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.RESULTS: In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response.CONCLUSIONS: Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.

U2 - 10.1245/s10434-020-08209-y

DO - 10.1245/s10434-020-08209-y

M3 - SCORING: Journal article

C2 - 32108923

VL - 27

SP - 3997

EP - 4006

JO - ANN SURG ONCOL

JF - ANN SURG ONCOL

SN - 1068-9265

IS - 10

ER -