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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5336-5337 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.5624
Predicting the Risk of Pancreatic Cancer: On CDKN2A Mutations in the Melanoma-Pancreatic Cancer Syndrome in ItalyDipartimento di Oncologia, Biologia e Genetica, Università di Genova, Genova, Italy
Istituto Nazionale per la Ricerca Sul Cancro, Genova, Italy
Dipartimento di Discipline Chirurgiche, Morfologiche e Metodologie Integrate, Università di Genova, Genova, Italy
Oncologia Medica, Ospedale San Martino, Genova, Italy
Unità di Gastroenterologia, Ospedale Galliera, Genova, Italy
Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
Dipartimento di Oncologia, Biologia e Genetica, Università di Genova, Genova, Italy To the Editor: We read with great interest the article by Wang and colleagues in the April 10, 2007, issue of the Journal of Clinical Oncology, describing PancPRO, a risk prediction model for pancreatic cancer (PC).1 Using family history of PC, PancPRO estimates the probability that an individual carries a mutation in a PC susceptibility gene and that an asymptomatic individual will develop PC. The authors validated the model using the largest available registry of PC, and found that it provided accurate risk assessment, suggesting that such a risk assessment is possible even when the causative genes are not known. Wang et al concluded that the next step in expanding PancPRO is to separately model the effects of mutations in genes that are known to be involved in susceptibility to PC. Mutations in the CDKN2A gene are known to underlie cancer susceptibility in the familial atypical mole multiple melanoma (FAMMM)/melanoma-PC syndrome. An increased risk of developing PC has been established in a subset of melanoma and FAMMM families worldwide carrying mutations located in the CDKN2A gene and affecting both of its protein products, p16INK4A and p14ARF, or the p16INK4A protein alone.2-9 The association between specific CDKN2A mutations and predisposition to specific cancers, however, still remains to be clarified. Indeed, a recent study by GenoMEL, the Melanoma Genetics Consortium, analyzed the largest sample of high-risk melanoma kindreds available to date. While it confirmed the association between PC and CDKN2A alterations impairing both p16INK4A and p14ARF, results differed by mutation,10 emphasizing that there is still much to be clarified before the effect of specific CDKN2A mutations can be incorporated into risk estimate tools such as PancPRO. Further, understanding individual risk of PC requires that studies be carried out, in which individuals rather than families be classified according to their mutational status.11 As a step in this direction, we have conducted a hospital-based case-control study of PC, and performed germline CDKN2A testing (including exon 1ß) in 120 unselected PC patients. In the first stage of the study,7 48 patients were analyzed and 4% (n = 2) were found to carry the CDKN2A G101W mutation, which affects both p16INK4A and p14ARF. We have now tested 72 additional cases and found the same 4% frequency (n = 3) of CDKN2A mutation, although the alterations identified, the E27X founder mutation and L65P, are known to affect p16INK4A alone. Interestingly, both E27X and L65P have been previously described in melanoma patients,12,13 but not in PC cases. The two E27X-positive patients share the same eight-marker haplotype at 9p21 observed in previously studied E27X-positive kindreds, and live in the same area in northwestern Italy.12 Overall, seven of 120 patients reported having a first-degree relative affected by PC, and one of those seven was mutation-positive (Fig 1). The family history of the five mutation-positive patients reflected the phenotypic variation seen in many melanoma-PC kindreds6: one of the two E27X-positive cases had a first-degree relative with PC, while the other was apparently nonfamilial; of the two G101W-positive individuals, one belonged to a melanoma-PC family, while the other seemed to be sporadic, and the case who carried L65P belonged to a melanoma-PC kindred.
Compared with the estimate that roughly 10% of PC cases are attributable to hereditary cancer syndromes overall,14 the 4% frequency of CDKN2A mutation we found in our series is remarkably high and may be explained by the fact that the CDKN2A founder mutations identified are prevalent in our region. Our findings are not sufficient enough to provide conclusive evidence as to whether CDKN2A mutations associated with PC alter only p16INK4A or both p16INK4A and p14ARF; indeed, among our five CDKN2A-positive patients, two carried G101W, which impairs both p16INK4A and p14ARF, and three harbored E27X or L65P, both of which affect p16INK4A only. Further case-control studies, possibly in areas where CDKN2A founder mutations play a lesser role, are needed to answer this question. However, because we identified these mutations in unselected PC patients rather than in high-risk melanoma or melanoma-PC families, we conclude that there likely exists an unbiased association between these particular mutations and PC. Finally, these results suggest that PC risk prediction models incorporating the effect of CDKN2A mutations will need to take into account the phenotypic diversity of inherited PC when a single causative gene is involved, as well as the variety of causative loci. Furthermore, the family history of our mutation-positive PC patients indicates that limited family structure and questions of penetrance may obscure familial ties, jeopardizing the accuracy of risk prediction based on family history alone. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We are grateful to all the participating patients, whose generous cooperation made this study possible, and to the nurses and physicians (including G. Bodini, C. Gambaro and V. Segalla) who referred and interviewed patients. REFERENCES
1. 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 2. Bergman W, Watson P, de Jong J, et al: Systemic cancer and the FAMMM syndrome. Br J Cancer 61:932-936, 1990[Medline] 3. 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 4. Borg A, Sandberg T, Nilsson K, et al: High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 92:1260-1266, 2000 5. Vasen HF, Gruis NA, Frants RR, et al: Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16 LEIDEN). Int J Cancer 87:809-811, 2000[CrossRef][Medline] 6. Lynch HT, Brand RE, Hogg D, et al: Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families. Cancer 94:84-96, 2002[CrossRef][Medline] 7. Ghiorzo P, Pastorino L, Bonelli L, et al: INK4/ARF germline alterations in pancreatic cancer patients. Ann Oncol 15:70-78, 2004 8. Goldstein AM: Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat 23:630, 2004[Medline] 9. Lynch HT, Fusaro RM, Lynch JF: Hereditary cancer syndrome diagnosis: Molecular genetic clues and cancer control. Future Oncol 3:169-181, 2007[CrossRef][Medline] 10. Goldstein AM, Chan M, Harland M, et al: Melanoma Genetics Consortium (GenoMEL): High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 66:9818-9828, 2006 11. Goldstein AM, Struewing JP, Fraser MC, et al: Prospective risk of cancer in CDKN2A germline mutation carriers. J Med Genet 41:421-424, 2004 12. Ghiorzo P, Gargiulo S, Pastorino L, et al: Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma. Hum Mol Genet 15:2682-2689, 2006 13. Landi MT, Goldstein AM, Tsang S, et al: Genetic susceptibility in familial melanoma from northeastern Italy. J Med Genet 41:557-566, 2004 14. Habbe N, Langer P, Sina-Frey M, et al: Familial pancreatic cancer syndromes. Endocrinol Metab Clin North Am 35:417-430, 2006[CrossRef][Medline]
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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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