DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

Dong, Xiaoqun; Li, Yanan; Hess, Kenneth R.; Abbruzzese, James L.; Li, Donghui

doi:10.1634/theoncologist.2010-0127

Cited by 66 publications

(27 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result does little to resolve the ambiguity in the literature surrounding the prognosis of mismatch repairdeficient pancreatic ductal adenocarcinomas, with select reports showing no prognostic value, 19,22 and other studies suggesting mismatch repair status is a prognostic marker in pancreatic ductal adenocarcinoma. 18,20,21 The incongruent nature of the studies mentioned above may be explained by the relatively small sample size used and the heterogeneity in treatments applied across studies. Of note, this study and Ottenhoffe et al 19 used immunohistochemistry on tissue microarray to assess mismatch repair status, yet significant prognostic value has only previously been correlated to mismatch repair status as defined at the DNA level by microsatellite instability assessment 18,20 and other methods.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, this study and Ottenhoffe et al 19 used immunohistochemistry on tissue microarray to assess mismatch repair status, yet significant prognostic value has only previously been correlated to mismatch repair status as defined at the DNA level by microsatellite instability assessment 18,20 and other methods. 21 The cohort used in this study is uniquely positioned to address treatment efficacy because of the large number of untreated cases, which serve as a control group. Unlike in mismatch repair-proficient pancreatic ductal adenocarcinomas, none of the clinico-pathologic covariates examined demonstrated independent prognostic significance in mismatch repair-deficient group.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] There is conflicting evidence regarding the prognostic value of mismatch repair status in pancreatic ductal adenocarcinoma. [18][19][20][21][22] One study, analyzing pancreatic ductal adenocarcinomas from 78 patients, found no prognostic significance associated with mismatch repair status. 19 In contrast, Dong et al 21 have shown that somatic variants in mismatch repair genes are positively correlated with increased overall survival, supporting earlier studies that suggested microsatellite instability (a surrogate marker of mismatch repair status) is prognostically important in pancreatic ductal adenocarcinoma.…”

mentioning

confidence: 99%

“…[18][19][20][21][22] One study, analyzing pancreatic ductal adenocarcinomas from 78 patients, found no prognostic significance associated with mismatch repair status. 19 In contrast, Dong et al 21 have shown that somatic variants in mismatch repair genes are positively correlated with increased overall survival, supporting earlier studies that suggested microsatellite instability (a surrogate marker of mismatch repair status) is prognostically important in pancreatic ductal adenocarcinoma. 18,20 Moreover, in contrast with colorectal cancer, the predictive value of mismatch repair status for treatment with pyrimidine analogs has not yet been studied in pancreatic ductal adenocarcinoma.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

et al. 2015

View full text Add to dashboard Cite

Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable diseasespecific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P ≤ 0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repairdeficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P = 0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repairdeficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is Pancreatic ductal adenocarcinoma is among the deadliest solid cancers, with little improvement in overall survival achieved in the past few decades. 1-3 Lack of effective screening modalities and late presentation with advanced stage disease result in fewer than 20% of patients being eligible for surgical resection. 4 Even in surgically-treated patients, the 5-year survival rate is lower than 20%, 5 highlighting the need for more effective and personalized systemic therapeutic approaches. Adjuvant chemotherapy is considered the standard of care for patients with resectable pancreatic ductal adenocarcinoma. 6,7 Pyrimidine analogs (gemcitabine or 5-fluorouracil (5-FU)) are the most commonly used agents, with gemcitabine demonstrating an improved survival compared with no treatment in 7 and an improved toxicity profile compared with 5-FU in ESPAC-3. 8 Molecular studies have shown that pancreatic ductal adenocarcinomas contain a high number of

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Previous studies have reported that DNA repair gene polymorphisms contribute to the development of pancreatic cancer (Li et al, 2009;Dong et al, 2011Dong et al, , 2012. There are several types of DNA damge, such as double-strand breaks (DSBs).…”

Section: Introductionmentioning

confidence: 99%

Association between single nucleotide polymorphisms of X-ray repair cross-complementing protein 4 gene and development of pancreatic cancer

Ding¹,

Ln²

2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. We performed a study to evaluate X-ray repair crosscomplementing protein 4 (XRCC4) gene polymorphisms and the development of pancreatic cancer. A case-control study including 206 patients with newly diagnosed primary pancreatic cancer and 412 controls was performed between January 2011 and October 2013 in a Chinese population. Genotypes of XRCC4 rs1805377, rs2075685, rs2075686 and rs1056503 were determined using polymerase chain reaction combined with a restriction fragment length polymorphism assay. Compared with controls, pancreatic cancer patients were more likely to have a higher body mass index, family history of cancer, and a habit of alcohol drinking compared with controls (P < 0.05). Logistic regression analysis showed that individuals carrying the TT genotype of XRCC4 rs2075685 had an increased risk of pancreatic cancer compared to those with the GG genotype, with an odds ratio (95% confidence interval) of 1.88 (1.15-3.08 XRCC4 rs2075685 polymorphism could influence the susceptibility to pancreatic cancer in a Chinese population.

show abstract