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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5337-5338 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.5731
In ReplyDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Departments of Environmental Health Sciences and Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center; and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center; and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center; and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD In our recent article, " Development and Validation of a Risk Assessment Tool for Individuals With a Family History of Pancreatic Cancer: PancPRO," we describe the first risk prediction tool for pancreatic cancer, which is modeled using a common penetrance for all dominant-acting pancreatic cancer susceptibility genes and a combined frequency of 0.35% for these variants.1 While approximately 10% of patients with pancreatic cancer report a family history of this disease, the majority of the genetic basis of this familial clustering remains unknown. However, some known genes, most notably, BRCA22-4 and CDKN2A,5-7 have been demonstrated to cause the familial clustering of pancreatic cancer. While our model did perform well in our large sample of 961 families with pancreatic cancer, we discuss how incorporation of the independent effects of both known and unknown pancreatic cancer susceptibility loci is a natural next step for our model.8 The letter by Ghiorzo et al provides further examination of the role of CDKN2A mutations in pancreatic cancer kindreds. This is an important step in understanding the role of these mutations in pancreatic cancer susceptibility and in ultimately incorporating these findings into risk prediction software. The majority of studies that have examined the role of CKDN2A in pancreatic cancer examined families with familial atypical multiple mole melanoma (FAMMM) due to CDKN2A mutations, to report an excess risk of pancreatic cancer,6,7 while very few studies have examined the role of CDKN2A mutations among families ascertained based on pancreatic cancer alone. Moskaluk et al examined 21 families with familial pancreatic cancer (a kindred with a least two first-degree relatives with pancreatic cancer) and reported a novel mutation in CDKN2A occurring in one of these families.7 They noted that while the family did not meet the definition of familial melanoma, it did include a member with melanoma. While Ghiorzo et al reported that some of the individuals they identified with germline CDKN2A mutations lacked a reported personal or family history of melanoma, careful skin examination by an expert dermatologist is needed to rule out subclinical disease in these relatives. Ghiorzo et al found the prevalence of mutation in CDKN2A of 4% among patients with pancreatic cancer, which is remarkable and deserves further study, as the authors state the high mutation prevalence may be due to founder mutations in the CDKN2A gene in this population. While sequence analysis of CDKN2A mutations has not been conducted for all families used in the development and validation of the PancPRO model, only one of the 287 families included in the segregation analysis used in the development of PancPRO and one of the 961 families used in the validation set for PancPRO provided a family history indicative of FAMMM syndrome.1,8 This suggests that the prevalence of CDKN2A mutations in the National Familial Pancreatic Tumor Registry may be low. Nervertheless, as we briefly highlight in the discussion section of our initial manuscript, obtaining a complete family history is an important step in the management of all hereditary cancer syndromes. While at this time the PancPRO model does not directly incorporate a family history of melanoma, if a family reports a history of both pancreatic cancer and melanoma, one should consider the potential for CDKN2A mutations as the source of disease in these families. Furthermore, as the genetic basis of familial pancreatic cancer and the overlap between hereditary cancer syndromes becomes better elucidated through studies such as that of Ghiorzo et al, our PancPRO model will evolve as well. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Klein AP, Beaty TH, Bailey-Wilson JE, et al: Evidence for a major gene influencing risk of pancreatic cancer. Genet Epidemiol 23:133-149, 2002[CrossRef][Medline] 2. Goggins M, Schutte M, Lu J, M, et al: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360-5364, 1996 3. Murphy KM, Brune KA, Griffin C, et al: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Res 62:3789-3793, 2002 4. Couch FJ, Johnson MR, Rabe KG, et al: The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16:342-346, 2007 5. Goldstein AM, Fraser MC, Struewing JP, et al: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333:970-974, 1995 6. Goldstein AM, Chan M, Harland M, et al: High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 66:9818-9828, 2006 7. Moskaluk CA, Hruban RH, Kern SE: P16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57:2140-2143, 1997 8. Wang W, Chen S, Brune KA, et al: PancPRO: Risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol 25:1417-1422, 2007 Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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