Affiliations of authors:M. M. Lerch, P. Simon, W. Domschke, Department of Medicine B, Westfälische Wilhelms-Universität, Münster, Germany; I. Ellis, N. Howes, S. Rutherford, J. P. Neoptolemos, European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer, University of Liverpool, U.K.; D. C. Whitcomb, Departments of Medicine, Cell Biology and Physiology, and Human Genetics, University of Pittsburgh, PA; V. Keim, Department of Medicine II, Universität Leipzig, Germany; C. W. Imrie, Surgical Unit, Royal Infirmary, Glasgow, U.K.
Correspondence to: Markus M. Lerch, M.D., Department of Medicine B, Westfälische Wilhelms-Universität, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany (e-mail: markus.lerch{at}uni-muenster.de).
Hereditary pancreatitis is an autosomal dominant disorder whose phenotype is associated with distinct point mutations in the cationic trypsinogen gene on chromosome 7q35 (1,2). Affected patients have recurrent episodes of pancreatitis that often begin during childhood. Compared with the general population or patients with chronic pancreatitis of common etiologies who have a somewhat increased cancer risk (3), patients with hereditary pancreatitis have a risk of developing pancreatic carcinoma that approaches 40% (4). Because all previously reported cases of pancreatic cancer associated with hereditary pancreatitis were diagnosed in patients who had inherited the disease from their father, the cumulative risk of developing cancer of the pancreas is considered to be even greater (approximately 75%) when hereditary pancreatitis is inherited from the father (4). In this correspondence, we report two kindreds with hereditary pancreatitis, each of which were affected by an R117H mutation of the trypsinogen gene, and in each case the patient with pancreatic cancer had inherited the defective cationic trypsinogen gene from the mother.
When informed consent for genetic testing was obtained, R117H mutations were identified
by the characteristic band pattern on ethidium bromide-stained agarose gels after AflIII
digestion of leukocyte DNA and confirmed by DNA sequencing as previously reported (1). In family 1 from the U.K. (Fig. 1, A), patient
I:2 and her daughter II:2 had recurrent pancreatitis and, therefore, were tested for mutations of
the typsinogen gene. When patient II:2 underwent abdominal surgery for complications of
hereditary pancreatitis, biopsy specimens were taken from the pancreas and paraffin sections
revealed a poorly differentiated adenocarcinoma. In family 2 (Fig. 1, B)
from Germany, the index patient III:14 had recurrent episodes of pancreatitis since early infancy.
Because his mother, aunt, and brother were all affected by similar symptoms, genetic testing was
performed and confirmed hereditary pancreatitis in all five subjects. His grandmother (I:2) and
uncle (II:3) had a lifetime history of chronic pancreatitis as well, and the latter died at age 49
years from histologically confirmed, metastatic ductal adenocarcinoma of the pancreas.
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NOTES
Medical record information and DNA of affected individuals have
been deposited with the German Hereditary Pancreatitis Registry, Leipzig, Germany; the
European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer; Liverpool, U.K.;
and the Midwest Multicenter Pancreatic Study Group, Pittsburgh, PA.
REFERENCES
1 Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141-5.[Medline]
2 Gorry MC, Gabbaizedeh D, Furey W, Gates LK Jr, Preston RA, Aston CE, et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997;113:1063-8.[Medline]
3 Ekbom A, McLaughlin JK, Karlsson BM, Nyren O, Gridley G, Adami HO, et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 1994;86:625-7.[Abstract]
4
Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates
LK Jr, Perrault J, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International
Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442-6.
5 Feinberg AP, Rainier S, DeBaun MR. Genomic imprinting, DNA methylation, and cancer. J Natl Cancer Inst Monogr 1995;17:21-6.[Medline]
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