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Absence of Deleterious Palladin Mutations in Patients with Familial Pancreatic Cancer

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Absence of Deleterious Palladin Mutations in Patients with Familial Pancreatic Cancer 1328 Null Results in Brief Absence of Deleterious Palladin Mutations in Patients with Familial Pancreatic Cancer Alison P. Klein,3,4 Michael Borges,1 Margaret Griffith,1 Kieran Brune,1 Seung-Mo Hong,1 Noriyuki Omura,1 Ralph H. Hruban,1,3 and Michael Goggins1,2,3 Departments of 1Pathology, 2Medicine, and 3Oncology, The Johns Hopkins University School of Medicine, and 4Department of Epidemiology, the Bloomberg School of Public Health, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland Abstract It has been reported that germline mutations in pancreatic cancer. We did not find any deleterious the palladin gene (PALLD) cause the familial aggre- mutations and find no evidence to implicate muta- gation of pancreatic cancer, but the evidence is tions in PALLD as a cause of familial pancreatic weak and controversial. We sequenced the coding cancer. (Cancer Epidemiol Biomarkers Prev 2009; regions of PALLD in 48 individuals with familial 18(4):1328–30) Introduction Brentnall et al. (1) identified a germline missense Materials and Methods alteration (P239S) in the palladin gene (PALLD)ina familial pancreatic cancer kindred and suggested that Forty-eight unrelated patients with familial pancreatic this variant may be a cause of the familial clustering cancer, defined as individuals with at least two first- of pancreatic cancer. Members of the kindred, known degree relatives with pancreatic cancer, were selected as family X, develop an early onset pancreatic cancer, from the National Familial Pancreatic Tumor Registry (9) with pancreatic insufficiency and diabetes mellitus in for analysis. DNA was obtained from EBV-transformed an autosomal dominant fashion (2) and have signifi- lymphocyte cell lines as previously described (10). PCR PALLD cant linkage to chromosome 4q32-34, a region that of (KIAA0992 Genbank # AB023209.1) was includes the PALLD gene (3). Brentnall et al. (1) impli- done mainly using primers designed for the pancreatic cated an oncogenic function for palladin after finding cancer genome project (11). Sequencing of PCR products overexpression of PALLD mRNA in pancreatic can- was done using the GenomeLab DTCS-Quick Start kit cer tissues. (Beckman-Coulter) according to the kit protocol. Prod- Since this original publication, subsequent studies ucts were sequenced using a CEQ 8000 GeXP Genetic have not found evidence to link palladin to familial Analysis System (Beckman-Coulter) and the sequence pancreatic cancer (4-8). However, these subsequent analysis was done with Sequencher v 4.1.4 (Gene Codes studies including linkage analysis, analyses of the Corporation). Putative single nucleotide polymorphisms PALLD P239Svariant in familial pancreatic cancer were evaluated by searching the single nucleotide cases, and examination of pancreatic cancer palladin polymorphism database at the National Center for expression have yet to evaluate the full sequence of Biotechnology Information/BLAST Web site. Over 92% PALLD in patients with familial pancreatic cancer (4-8). of the coding region was successfully sequenced. The To determine if sequence variants in PALLD could study was done with approval from our Institutional be contributing to pancreatic cancer susceptibility, Review Board. we sequenced the entire coding region of PALLD in 48 individuals with familial pancreatic cancer. Results No deleterious sequence variants were identified in any of the 48 patients with familial pancreatic cancer (97% confidence interval, 0-7.2%). Five single nucleotide poly- morphisms were identified, only one of which changed Received 1/20/09; accepted 1/30/09; published OnlineFirst 3/31/09. the amino acid sequence (S236G), the same variant that Grant support: National Cancer Institute grants Spore in Gastrointestinal Cancer was identified by Gallinger et al. (5) as a polymorphism (P50CA62924), the Pacgene Consortium (R01CA97075), R01CA120432, the V foundation, The Lustgarten Foundation for Pancreatic Cancer Research, and the having no association with pancreatic cancer. The Michael Rolfe Foundation. prevalence of this variant (c.236 A>G) in our study Requests for reprints: Michael Goggins, Cancer Research Building 2 Room 342, 1550 sample was not significantly different (GG, 0.42; AG, Orleans Street, Baltimore, MD, 21231. Phone: 410-955-3511; Fax: 410-614-0671. E-mail: [email protected] 0.44; AA, 0.14) to that previously reported in controls Copyright D 2009 American Association for Cancer Research. (GG, 0.39; AG, 0.47; AA, 0.14). The remaining variants doi:10.1158/1055-9965.EPI-09-0056 that we identified were all silent (see Table 1). Cancer Epidemiol Biomarkers Prev 2009;18(4). April 2009 Downloaded from cebp.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Cancer Epidemiology,Biomarkers & Prevention 1329 Table 1. PALLD sequence variants Exon Nucleotide change Amino acid change Frequency SNP database 2 c. 236 A > G Ser-Gly GG = 0.52 rs62333013 AG = 0.35 AA = 0.13 6 c. 467 A > T Ala-Ala AA = 0.81 No AT = 0.19 TT = 0 7 c. 492 A > G Arg-Arg AA = 0.90 rs1059444 AG = 0.02 GG = 0.08 12 n. 4019 G > A 3¶ UTR GG = 0.83 rs1136603 GA = 0.16 AA = 0.02 12 n. 4171 C > G 3¶ UTR CC = 0.18 rs1071738 CG = 0.39 GG = 0.46 Abbreviations: SNP, single nucleotide polymorphism; UTR, untranslated region. Discussion one from Europe and one from Canada (4, 5), for the P239S PALLD variant in pancreatic cancer families were Pancreatic cancer is a rapidly fatal disease and the fourth negative, and additional sequence analyses confined to leading cause of cancer death in the United States (12). the exon containing the P239Svariant identified only a Therefore, considerable efforts under way to discover common missense polymorphism adjacent to P239S(5). familial pancreatic cancer genes to help identify individ- Here, we extend these observation to additional uals at increased risk of developing the disease. patients and we sequence the entire coding sequence Approximately 5% to 10% of pancreatic cancer patients of the PALLD, and again, we find no deleterious muta- report a family history of pancreatic cancer (13). Germ- tions (5). Our results are consistent with the growing BRCA2, line mutations in several genes including body of evidence that germline alterations in the PALLD p16/CDKN2A, LKB1/STK11 PRSS1 , and have been shown gene are not a significant contributor to familial pan- to confer a significant lifetime risk of pancreatic cancer creatic cancer susceptibility (4-8). It is possible that either (14-19), but these mutations explain <10% of the familial germline PALLD mutations are a rare cause of familial aggregation of pancreatic cancer. Identifying the genetic pancreatic cancer, or that another gene within the 4q32- basis of familial pancreatic cancer can enable accurate 34 locus contributes to pancreatic cancer susceptibility estimation of cancer risk in mutation carriers (20) and in family X. Because the family X variant (P239S) and enable these carriers to participate in pancreatic screen- the common polymorphism (S236G) are in close proxi- ing protocols (21, 22). Early evidence indicates endo- mity, it is possible that the P239Svariant is not func- scopic ultrasound-based screening is an effective way tionally deleterious. to identify pancreatic cancer precursor neoplasms (23). In summary, DNA sequence analysis of the PALLD Additional research is needed to identify markers that gene in familial pancreatic cancers did not identify can facilitate the early detection of microscopic neo- any deleterious mutations that would support a role plasia among individuals undergoing screening (24, 25). for PALLD as a familial pancreatic cancer susceptibi- Furthermore, identifying the genetic basis of cancer can lity gene. have therapeutic implications. For example, cancers with inactivation of the BRCA2/Fanconi pathway are sensi- tive to DNA-crosslinking drugs including mitomycin-C Disclosure of Potential Conflicts of Interest and PARP inhibitors (26, 27). Brentnall et al. (1) recently reported that germline No potential conflicts of interest were disclosed. PALLD gene mutations may cause familial pancreatic cancer. A number of follow-up studies on PALLD have failed to implicate it as a significant cause of familial References pancreatic cancer (4-8). First, linkage analysis of familial 1. Pogue-Geile KL, Chen R, Bronner MP, et al. Palladin mutation causes pancreatic cancer kindreds from the PacGene consortium familial pancreatic cancer and suggests a new cancer mechanism. (8, 13) and European registries (7) did not identify PLoSMed 2006;3:e516. PALLD 2. Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early linkage to the locus, although these studies could diagnosis and treatment of pancreatic dysplasia in patients with not rule out linkage to this region in a minority of a family history of pancreatic cancer. Ann Intern Med 1999;131: families. Second, immunohistochemical labeling has 247–55. shown that the major splice variant of the palladin 3. Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromo- protein is not expressed at significant levels in neoplastic some 4q32-34. Am J Hum Genet 2002;70:1044 – 8. Epub 2002 Feb 27. cells but is instead expressed in the nonneoplastic 4. Slater E, Amrillaeva V, Fendrich V, et al. Palladin mutation causes stromal cells of pancreatic cancer (6). Third, the sequenc- familial pancreatic cancer: absence in European families. PLoSMed ing of the entire pancreatic cancer genome failed to iden- 2007;4:e164. tify any somatic mutations in PALLD (11) and therefore 5. Zogopoulos G, Rothenmund H, Eppel A, et al. The P239Spal- PALLD ladin variant does not account for a significant fraction of heredi- do not support the role of as a common onco- tary or early onset pancreas cancer. Hum Genet 2007;121:635 – 7. genic target of pancreatic cancers. Fourth, two searches, Epub 2007 Apr 6. Cancer Epidemiol Biomarkers Prev 2009;18(4). April 2009 Downloaded from cebp.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research.
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