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Vol. 5, No. 2-3, 2005
Issue release date: 2005
Section title: Original Paper
Pancreatology 2005;5:220–228
(DOI:10.1159/000085275)

Defective DNA Mismatch Repair in Long-Term (≥3 Years) Survivors with Pancreatic Cancer

Maple J.T. · Smyrk T.C. · Boardman L.A. · Johnson R.A. · Thibodeau S.N. · Chari S.T.
aDepartment of Internal Medicine, bDivision of Gastroenterology, cDepartment of Laboratory Medicine and Pathology, dDivision of Anatomic Pathology, and eDivision of Experimental Pathology and Laboratory Medicine, Mayo Clinic and Foundation, Rochester, Minn., USA

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 11/17/2003
Accepted: 8/2/2004
Published online: 5/9/2005

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 3

ISSN: 1424-3903 (Print)
eISSN: 1424-3911 (Online)

For additional information: http://www.karger.com/PAN

Abstract

Background/Aims: Defective DNA mismatch repair (MMR) in pancreatic cancer, reported in up to 13% of sporadic pancreatic cancers, may predict a good prognosis. To determine if long-term survival in pancreatic cancer could be attributed to defective DNA MMR, we ascertained its prevalence in 35 pancreatic cancer patients who survived ≧3 years after surgery. Methods: We performed immunohistochemistry (IHC) for MMR proteins hMLH1, hMSH2, and hMSH6 in all 35 tumors and microsatellite instability (MSI) studies in 34/35 tumors using 10 microsatellite markers in paired normal and tumor DNA. Defective DNA MMR was defined as absence of protein expression on IHC and/or MSI in ≧30% of markers studied. Results: On IHC, 3/35 (8.6%) tumors had defective DNA MMR. All 3 had absent expression of a DNA MMR protein (hMLH1 in 2 and hMSH2) and 2/3 also had MSI; the third could not be tested. Definitely 2, and probably all 3 patients had hereditary nonpolyposis colon cancer as determined by clinical and genetic profiles. Conclusion: Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer.



 

Editorial Comment



 

Pancreatic Ductal Adenocarcinoma: Microsatellite Instability, Familial Cancer Syndromes, and Medullary Histology


Francisco X. Real

Institut Municipal d’Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain

Pancreatic ductal adenocarcinoma (PDA) remains a formidable clinical challenge [1, 2]. Over the past 50 years, the prognosis of patients with PDA has remained essentially unchanged. The impact of advances leading to an early diagnosis (i.e. identification of tumors of 2 cm diameter) would likely be relatively small given that approximately two thirds of such tumors involve lymph nodes. The impact of therapeutic advances may also be limited due to age at presentation and poor condition of patients. However, there is room for optimism: (1) there have been major advances in the understanding of the biology of the gland [3], the molecular mechanisms involved in PDA [4], and in the development of mouse models of disease [5]; (2) the study of selected subsets of patients (i.e. hereditary PDA) may provide opportunities for improved prospects for a few individuals [6]; and (3) randomized trials support the notion that adjuvant chemotherapy provides a clinical benefit [7].

In this issue of Pancreatology, Maple et al. [8] analyze microsatellite instability (MI) in ‘long-term’ survivors (>3 years) with PDA. MI is the molecular hallmark of the inactivation of genes involved in mismatch repair, a characteristic of hereditary nonpolyposis colorectal cancer (HNPCC) as well as of some sporadic tumors [9]. The genes most commonly implicated in HNPCC, MLH1 and MSH2, are mainly inactivated through mutation and epigenetic silencing. The work of Maple et al. was prompted by prior reports suggesting that: (1) in PDA, MI is associated with medullary histology and wild-type K-ras [10, 11], (2) patients with MI+ tumors may have a stronger history of familial cancer [11], and (3) MI is associated with an improved prognosis [12, 13]. Maple et al. conclude that MI+ tumors are not over-represented among long-term survivors with PDA, that such tumors are commonly associated with a personal or familial history of cancer – possibly in the context of HNPCC – and that there is no straightforward association between MI+ tumors and medullary histology [8].

It is likely that the controversial findings on the subject can be accounted in part by undesired selection biases: the report of Goggins et al. [10] dealt with human PDA xenografted in nude mice; a subsequent report from the same group reported an analysis of 18 cases with medullary histology drawn from a series of ‘450 randomly chosen pancreatic cancers’ [11]; Yamamoto et al. [12] analyzed 100 cases undergoing surgical resection, not all of which had curative intent; and Nakata et al. [13] reported on 46 cases undergoing surgical resection. Now, Maple et al. [8] analyze 35 ‘long-term survivors’ drawn from a series of 373 patients undergoing surgical resection at a single institution. The scenario is reminiscent of the story of the blind men and the elephant: the subject of study is complex, the approach is fragmentary, and we lack a global view of the problem that can provide real understanding and progress.

The overall evidence reported in the literature strongly suggests that the identification of subgroups of PDA (i.e. MI+, medullary) may have clinical relevance. However, none of the reports published provides sufficient evidence to justify changes in clinical management.

We do not yet know why a few patients with PDA become long-term survivors. Such information may prove invaluable in designing strategies applicable in the future to many patients. What we now need are not a few more reports adding to the controversy but, rather, definitive studies. They should prospectively define the patient population, collect precise data on surgery, staging and therapy, determine the reproducibility of pathologists’ assessment of medullary carcinoma of the pancreas, carefully select the most appropriate molecular studies that need to be performed, and analyze the data with appropriate statistical tools.

There is now substantial evidence that adjuvant chemotherapy may improve the long-term survival of patients with PDA [7]. Such progress is facilitating recruitment of patients into clinical trials at a rapid pace: more than 600 cases have already entered the ESPAC-3 protocol. Such trials provide an exceptional opportunity to determine the value of molecular prognostic markers in well-characterized series of patients treated in a homogeneous manner.

References

1 American Gastroenterology Association position statement on epidemiology: Diagnosis, and treatment of pancreatic ductal carcinoma. Gastroenterology 1999;117:1463–1484.

2 Real FX: A ‘catastrophic hypothesis’ for pancreas cancer progression. Gastroenterology 2003;124:1958–1964.

3 Kim SK, MacDonald RJ: Signaling and transcriptional control of pancreatic organogenesis. Curr Opin Genet Dev 2002;12:540–547.

4 Jaffee EM, Hruban RH, Canto M, Kern SE: Focus on pancreas cancer. Cancer Cell 2002;2:25–28.

5 Leach SD: Mouse models of pancreatic cancer: The fur is finally flying! Cancer Cell 2004;5:7–11.

6 Rieder H, Bartsch DK: Familial pancreatic cancer. Fam Cancer 2004;3:69–74.

7 Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Buchler MW, European Study Group for Pancreatic Cancer: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200–1210.

8 Maple JT, Smyrk TC, Boardman LA, Johnson RA, Thibodeau SN, Chari ST: Defective DNA mismatch repair in long-term (≥3 years) survivors with pancreatic cancer. Pancreatology 2005;5:220–228 .

9 Lucci-Cordisco E, Zito I, Gensini F, Genuardi M: Hereditary nonpolyposis colorectal cancer and related conditions. Am J Med Genet 2003;122A:325–334.

10 Goggins M, Offerhaus GJA, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Am J Pathol 1998;152:1501–1507.

11 Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJA, Hruban RH, Kern SE: Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas. Am J Pathol 2000;156:1641–1651.

12 Yamamoto H, Itoh F, Nakamura H, Fushukima H, Sasaki S, Perucho M, Imai K: Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res 2001;61:3139–3144.

13 Nakata B, Wang YQ, Yashiro M, Nishioka N, Tanaka H, Ohira M, Ishikawa T, Nishino H, Hirakawa K: Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res 2002;8:2536–2540.

14 Neoptolemos J (personal communication, September 2004).

  

Author Contacts

Suresh T. Chari, MD
200 First St SW
Mayo Clinic
Rochester MN 55905 (USA)
Tel. +1 507 266 4347, Fax +1 507 284 5486, E-Mail chari.suresh@mayo.edu

  

Article Information

Received: November 17, 2003
Accepted after revision: August 2, 2004
Published online: April 22, 2005
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 3, Number of References : 38

  

Publication Details

Pancreatology

Vol. 5, No. 2-3, Year 2005 (Cover Date: 2005)

Journal Editor: Urrutia, R. (Rochester, Minn.)
ISSN: 1424–3903 (print), 1424–3911 (Online)

For additional information: http://www.karger.com/pan


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 11/17/2003
Accepted: 8/2/2004
Published online: 5/9/2005

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 3

ISSN: 1424-3903 (Print)
eISSN: 1424-3911 (Online)

For additional information: http://www.karger.com/PAN


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