Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 10/2020

Open Access 01-10-2020 | Pancreatic Cancer | Translational Research and Biomarkers

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

Authors: Christoph Fraune, MD, Eike Burandt, MD, Ronald Simon, PhD, Claudia Hube-Magg, PhD, Georgia Makrypidi-Fraune, PhD, Martina Kluth, PhD, Franziska Büscheck, MD, Doris Höflmayer, MD, Niclas Ch. Blessin, Tim Mandelkow, Wenchao Li, Daniel Perez, MD, Jakob R. Izbicki, MD, Waldemar Wilczak, MD, Guido Sauter, MD, Jörg Schrader, MD, Michael Neipp, MD, Hamid Mofid, MD, Thies Daniels, MD, Christoph Isbert, MD, Till S. Clauditz, MD, Stefan Steurer, MD

Published in: Annals of Surgical Oncology | Issue 10/2020

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
2.
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedPubMedCentralCrossRef
3.
Patnaik A, Kang SP, Rasco D, et al. Phase I study of pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286–93.PubMedCrossRef
4.
5.
Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—when a biomarker defines the indication. N Engl J Med. 2017;377(15):1409–12.PubMedCrossRef
6.
7.
Backes FJ, Leon ME, Ivanov I, et al. Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer. Gynecol Oncol. 2009;114(3):486–90.PubMedCrossRef
8.
Joehlin-Price AS, Perrino CM, Stephens J, et al. Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables. Gynecol Oncol. 2014;133(1):43–7.PubMedPubMedCentralCrossRef
9.
Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342–50.PubMedCrossRef
10.
11.
Kim JY, Shin NR, Kim A, et al. Microsatellite instability status in gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes. Korean J Pathol. 2013;47(1):28-35.PubMedPubMedCentralCrossRef
12.
Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-9.
13.
Mathiak M, Warneke VS, Behrens HM, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25(1):12–24.PubMedCrossRef
14.
Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017.
15.
Latham A, Srinivasan P, Kemel Y, et al. Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol. 2019;37(4):286–95.PubMedCrossRef
16.
17.
Andersen R, Donia M, Westergaard MC, Pedersen M, Hansen M, Svane IM. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma. Hum Vaccin Immunother. 2015;11(12):2790–5.PubMedPubMedCentralCrossRef
18.
Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8 + lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.PubMedCrossRef
19.
Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91(12):2417–22.PubMedCrossRef
20.
Buckowitz A, Knaebel HP, Benner A, et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer. 2005;92(9):1746–53.PubMedPubMedCentralCrossRef
21.
Suemori T, Susumu N, Iwata T, et al. Intratumoral CD8 + lymphocyte infiltration as a prognostic factor and its relationship with cyclooxygenase 2 expression and microsatellite instability in endometrial cancer. Int J Gynecol Cancer. 2015;25(7):1165–72.PubMedCrossRef
22.
Eatrides JM, Coppola D, Al Diffalha S, Kim RD, Springett GM, Mahipal A. Microsatellite instability in pancreatic cancer. J Clin Oncol. 2016 2016;34(15_suppl, e15753).
23.
Tomaszewska R, Okon K, Stachura J. Expression of the DNA mismatch repair proteins (hMLH1 and hMSH2) in infiltrating pancreatic cancer and its relation to some phenotypic features. Pol J Pathol. 2003;54(1):31–7.PubMed
24.
Ghimenti C, Tannergard P, Wahlberg S, et al. Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer. 1999;80(1–2):11–6.PubMedPubMedCentralCrossRef
25.
Nakata B, Wang YQ, Yashiro M, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002;8(8):2536–40.PubMed
26.
Joost P, Veurink N, Holck S, et al. Heterogenous mismatch-repair status in colorectal cancer. Diagn Pathol. 2014;9:126.
27.
Chapusot C, Martin L, Bouvier AM, et al. Microsatellite instability and intratumoural heterogeneity in 100 right-sided sporadic colon carcinomas. Br J Cancer. 2002;87(4):400–4.PubMedPubMedCentralCrossRef
28.
Watson N, Grieu F, Morris M, et al. Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer. J Mol Diagn. Sep 2007;9(4):472–8.PubMedPubMedCentralCrossRef
29.
Watkins JC, Nucci MR, Ritterhouse LL, Howitt BE, Sholl LM. Unusual mismatch repair immunohistochemical patterns in endometrial carcinoma. Am J Surg Pathol. 2016;40(7):909-16.PubMedCrossRef
30.
Pai RK, Plesec TP, Abdul-Karim FW, et al. Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: molecular and morphologic analysis of 6 cases. Am J Surg Pathol. 2015;39(7):993–9.PubMedCrossRef
31.
Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4(7):844–7.PubMedCrossRef
32.
R-Core-Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.2018.
33.
Hinsch A, Brolund M, Hube-Magg C, et al. Immunohistochemically detected IDH1(R132H) mutation is rare and mostly heterogeneous in prostate cancer. World J Urol. 2018;36(6):877–82.PubMedCrossRef
34.
Simon R, Panussis S, Maurer R, et al. KIT (CD117)-positive breast cancers are infrequent and lack KIT gene mutations. Clin Cancer Res. 2004;10(1 Pt 1):178–183.PubMedCrossRef
35.
Salem ME, Puccini A, Grothey A, et al. Landscape of tumor mutation load, mismatch repair deficiency, and pd-l1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16(5):805–12.PubMedPubMedCentralCrossRef
36.
Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326–36.PubMedPubMedCentralCrossRef
37.
Riazy M, Kalloger SE, Sheffield BS, et al. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Mod Pathol. 2015;28(10):1383-9.PubMedCrossRef
38.
Lupinacci RM, Goloudina A, Buhard O, et al. Prevalence of microsatellite instability in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2018;154(4):1061–5.PubMedCrossRef
39.
Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol. 2000;156(5):1641–51.PubMedPubMedCentralCrossRef
40.
Fraune C, Simon R, Hoflmayer D, et al. High homogeneity of mismatch repair deficiency in advanced prostate cancer. Virchows Arch. 2019.
41.
Liu W, Shia J, Gonen M, Lowery MA, O’Reilly EM, Klimstra DS. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014;43(8):1264–70.PubMedCrossRef
42.
Agaram NP, Shia J, Tang LH, Klimstra DS. DNA mismatch repair deficiency in ampullary carcinoma: a morphologic and immunohistochemical study of 54 cases. Am J Clin Pathol. 2010;133(5):772–80.PubMedCrossRef
43.
Acharya S, Wilson T, Gradia S, et al. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A. 1996;93(24):13629–34.PubMedPubMedCentralCrossRef
44.
Nielsen SV, Stein A, Dinitzen AB, et al. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations. PLoS Genet. 2017;13(4):e1006739.PubMedPubMedCentralCrossRef
45.
Marra G, Iaccarino I, Lettieri T, Roscilli G, Delmastro P, Jiricny J. Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proc Natl Acad Sci U S A. 1998;95(15):8568–73.PubMedPubMedCentralCrossRef
46.
Chang DK, Ricciardiello L, Goel A, Chang CL, Boland CR. Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000;275(24):18424–31.PubMedCrossRef
47.
Cho J, Kang SY, Kim KM. MMR protein immunohistochemistry and microsatellite instability in gastric cancers. Pathology. 2019;51(1):110–3.PubMedCrossRef
48.
Lee HJ, Jang YJ, Lee EJ, et al. The significance of mismatch repair genes in gastric cancer. J Cancer Res Ther. 2013;9(1):80–3.CrossRef
49.
Metcalf AM, Spurdle AB. Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review. Fam Cancer.2014;13(1):1–12.PubMedCrossRef
50.
Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am J Surg Pathol. 2014;38(11):1501–9.PubMedPubMedCentralCrossRef
51.
Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. Aug 1 1998;58(15):3455–60.PubMed
52.
Slavin TP, Neuhausen SL, Nehoray B, et al. The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Fam Cancer. 2018;17(2):235–45.PubMedPubMedCentralCrossRef
53.
Bartley AN, Luthra R, Saraiya DS, Urbauer DL, Broaddus RR. Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing. Cancer Prev Res (Phila). 2012;5(2):320–7.PubMedCrossRef
54.
Cicek MS, Lindor NM, Gallinger S, et al. Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry. J Mol Diagn. May 2011;13(3):271–81.PubMedPubMedCentralCrossRef
55.
Engel C, Forberg J, Holinski-Feder E, et al. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2006;118(1):115–22.PubMedCrossRef
56.
Berends MJ, Wu Y, Sijmons RH, et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. Jan 2002;70(1):26-37.PubMedCrossRef
57.
Umar A, Risinger JI, Glaab WE, Tindall KR, Barrett JC, Kunkel TA. Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics. 1998;148(4):1637–46.PubMedPubMedCentralCrossRef
58.
Boland CR, Thibodeau SN, Hamilton SR, et al. A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248–57.PubMed
59.
Schuster-Bockler B, Lehner B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature. 2012;488(7412):504–7.PubMedCrossRef
60.
61.
De Rosa S, Sahnane N, Tibiletti MG, et al. EBV(+) and MSI Gastric Cancers Harbor High PD-L1/PD-1 Expression and High CD8(+) Intratumoral Lymphocytes. Cancers (Basel). 2018;10(4).
62.
IASLC. IASLC Atlas of ALK and ROS1 testing in Lung Cancer Editorial Rx Press; Second Edition, 2016.
63.
64.
Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018;7(3):746–56.PubMedPubMedCentralCrossRef
65.
Salipante SJ, Scroggins SM, Hampel HL, Turner EH, Pritchard CC. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60(9):1192–9.PubMedCrossRef
66.
Masugi Y, Abe T, Ueno A, et al. Characterization of spatial distribution of tumor-infiltrating CD8(+) T cells refines their prognostic utility for pancreatic cancer survival. Mod Pathol. 2019;32(10):1495–507.PubMedCrossRef
67.
Hou YC, Chao YJ, Hsieh MH, Tung HL, Wang HC, Shan YS. Low CD8(+) t cell infiltration and high pd-l1 expression are associated with level of cd44(+)/cd133(+) cancer stem cells and predict an unfavorable prognosis in pancreatic cancer. Cancers (Basel). 2019;11(4).
68.
Miksch RC, Schoenberg MB, Weniger M, et al. Prognostic Impact of Tumor-Infiltrating Lymphocytes and Neutrophils on Survival of Patients with Upfront Resection of Pancreatic Cancer. Cancers (Basel). 2019;11(1).
69.
70.
Tahkola K, Mecklin JP, Wirta EV, et al. High immune cell score predicts improved survival in pancreatic cancer. Virchows Arch. 2018;472(4):653–65.
Metadata
Title
MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes
Authors
Christoph Fraune, MD
Eike Burandt, MD
Ronald Simon, PhD
Claudia Hube-Magg, PhD
Georgia Makrypidi-Fraune, PhD
Martina Kluth, PhD
Franziska Büscheck, MD
Doris Höflmayer, MD
Niclas Ch. Blessin
Tim Mandelkow
Wenchao Li
Daniel Perez, MD
Jakob R. Izbicki, MD
Waldemar Wilczak, MD
Guido Sauter, MD
Jörg Schrader, MD
Michael Neipp, MD
Hamid Mofid, MD
Thies Daniels, MD
Christoph Isbert, MD
Till S. Clauditz, MD
Stefan Steurer, MD
Publication date
01-10-2020
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 10/2020
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-08209-y

Other articles of this Issue 10/2020

Annals of Surgical Oncology 10/2020 Go to the issue

Health Services Research and Global Oncology

Warm and Welcoming: Is It What We Say or How We Say It?

Sarcoma

The Landmark Series: Systemic Therapy for Resectable Gastrointestinal Stromal Tumors

Pancreatic Tumors

Does Site Matter? Impact of Tumor Location on Pathologic Characteristics, Recurrence, and Survival of Resected Pancreatic Ductal Adenocarcinoma

ASO Author Reflections

ASO Author Reflections: Elevated Preoperative Specific Growth Rate is Associated with Shortened Survival After Resection for Pancreatic Neuroendocrine Tumors

Thoracic Oncology

Long-Term Outcomes of Pulmonary Metastasectomy for Uterine Malignancies: A Multi-institutional Study in the Current Era

ASO Author Reflections

ASO Author Reflections: Breast Cancer Detection of Baseline Screening MRI in High-Risk Women Who Are Not in the Highest Risk Groups