Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds with p16INK4 Mutations
Alisa M. Goldstein, Ph.D., Mary C. Fraser, R.N., M.A., Jeffery P. Struewing, M.D., M.S., Christopher J. Hussussian, M.D., Koustubh Ranade, Ph.D., Deborah P. Zametkin, M.S.N., Laura S. Fontaine, B.S.N., Sara M. Organic, B.A., Nicholas C. Dracopoli, Ph.D., Wallace H. Clark, M.D., and Margaret A. Tucker, M.D.
Background A gene on chromosome 9p, p16INK4, has been implicatedin the pathogenesis of cutaneous malignant melanoma in 19 melanoma-pronefamilies. In 10 of these kindreds mutations that impaired thefunction of the p16INK4 protein (p16M alleles) cosegregatedwith the disease. By contrast, in the other nine kindreds themutation did not alter the function of p16INK4 (p16W alleles).We looked for differences in clinical and genetic epidemiologicfeatures in these two groups of families.
Methods We compared the median ages at diagnosis of melanoma,number of melanomas, thickness of the tumors, and number ofnevi in the kindreds. We estimated prospectively the risks ofmelanoma or other cancers in families followed for 6 to 18 yearsand the risks of other cancers since 1925 (the entire period)by comparing the number of cancer cases observed with the numberexpected.
Results The risk of invasive melanoma was increased by a factorof 75 in kindreds with p16M alleles and a factor of 38 in kindredswith p16W alleles. Although this difference was not significant(P = 0.14), there was a striking difference in the risk of othertumors. In kindreds with p16M alleles, the risk of pancreaticcancer was increased by a factor of 13 in the prospective period(2 cases observed, 0.15 expected; standardized incidence ratio,13.1; 95 percent confidence interval, 1.5 to 47.4) and by afactor of 22 in the entire period (7 cases observed, 0.32 expected;standardized incidence ratio, 21.8; 95 percent confidence interval,8.7 to 44.8). In contrast, we found no cases of pancreatic cancerin kindreds with p16W alleles.
Conclusions The development of pancreatic cancer in kindredsprone to melanoma may require a p16M mutation. Genetic factors,such as the kind of mutation found in p16INK4, may explain theinconsistent occurrence of other cancers in these kindreds.
Source Information
From the Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Md. (a.M.G., M.C.F., J.P.S., S.M.O., M.A.T.); the Department of Nursing, Warren G. Magnuson Clinical Center, Bethesda, Md. (M.C.F.); the National Center for Human genome Research, National Institutes of Health, Bethesda, md. (J.P.S., C.J.H., K.R., N.C.D.); the Department of Surgery, Washington University School of Medicine, St. Louis (C.J.H.); Westat, Inc., Rockville, Md. (D.P.Z.); Battelle/SRA, Rockville, Md. (L.S.F.); Sequana Therapeutics, Inc., La Jolla, Calif. (N.C.D.); the Pigmented Lesion Study Group and Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia (W.H.C.); and the Department of Pathology, Beth Israel Hospital, Harvard Medical School, Boston (W.H.C.).
Address reprint requests to Dr. Goldstein at Genetic Epidemiology Branch, Executive Plaza North, Rm. 439, 6130 Executive Blvd., MSC 7372, Bethesda, MD 20892-7372.
Familial Melanoma and Pancreatic Cancer
Ciotti P., Strigini P., Bianchi-Scarrà G., Wright F. A., Thomas R. G., Bergman W., Gruis N., Goldstein A. M., Tucker M. A., Whelan A. J., Bartsch D., Goodfellow P. J.
Extract |
Full Text
N Engl J Med 1996;
334:469-472, Feb 15, 1996.
Correspondence
This article has been cited by other articles:
Ghiorzo, P., Gargiulo, S., Nasti, S., Pastorino, L., Battistuzzi, L., Bruno, W., Bonelli, L., Taveggia, P., Pugliese, V., Borgonovo, G., Mastracci, L., Fornarini, G., Romagnoli, P., Iiritano, E., Savarino, V., Bianchi-Scarra, G.
(2007). Predicting the Risk of Pancreatic Cancer: On CDKN2A Mutations in the Melanoma-Pancreatic Cancer Syndrome in Italy. JCO
25: 5336-5337
[Full Text]
Wang, W., Chen, S., Brune, K. A., Hruban, R. H., Parmigiani, G., Klein, A. P.
(2007). In Reply. JCO
25: 5337-5338
[Full Text]
Brand, R. E, Lerch, M. M, Rubinstein, W. S, Neoptolemos, J. P, Whitcomb, D. C, Hruban, R. H, Brentnall, T. A, Lynch, H. T, Canto, M. I, Participants of the Fourth International Symposium,
(2007). Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut
56: 1460-1469
[Abstract][Full Text]
Wang, W., Chen, S., Brune, K. A., Hruban, R. H., Parmigiani, G., Klein, A. P.
(2007). PancPRO: Risk Assessment for Individuals With a Family History of Pancreatic Cancer. JCO
25: 1417-1422
[Abstract][Full Text]
Couch, F. J., Johnson, M. R., Rabe, K. G., Brune, K., de Andrade, M., Goggins, M., Rothenmund, H., Gallinger, S., Klein, A., Petersen, G. M., Hruban, R. H.
(2007). The Prevalence of BRCA2 Mutations in Familial Pancreatic Cancer. Cancer Epidemiol. Biomarkers Prev.
16: 342-346
[Abstract][Full Text]
Goldstein, A. M, Chan, M., Harland, M., Hayward, N. K, Demenais, F., Timothy Bishop, D, Azizi, E., Bergman, W., Bianchi-Scarra, G., Bruno, W., Calista, D., Cannon Albright, L. A, Chaudru, V., Chompret, A., Cuellar, F., Elder, D. E, Ghiorzo, P., Gillanders, E. M, Gruis, N. A, Hansson, J., Hogg, D., Holland, E. A, Kanetsky, P. A, Kefford, R. F, Teresa Landi, M., Lang, J., Leachman, S. A, MacKie, R. M, Magnusson, V., Mann, G. J, Newton Bishop, J., Palmer, J. M, Puig, S., Puig-Butille, J. A, Stark, M., Tsao, H., Tucker, M. A, Whitaker, L., Yakobson, E., The Lund Melanoma Study Group, , and the Melanoma Genetics Consortium (GenoMEL),
(2007). Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet.
44: 99-106
[Abstract][Full Text]
Goldstein, A. M., Chan, M., Harland, M., Gillanders, E. M., Hayward, N. K., Avril, M.-F., Azizi, E., Bianchi-Scarra, G., Bishop, D. T., Bressac-de Paillerets, B., Bruno, W., Calista, D., Cannon Albright, L. A., Demenais, F., Elder, D. E., Ghiorzo, P., Gruis, N. A., Hansson, J., Hogg, D., Holland, E. A., Kanetsky, P. A., Kefford, R. F., Landi, M. T., Lang, J., Leachman, S. A., MacKie, R. M., Magnusson, V., Mann, G. J., Niendorf, K., Newton Bishop, J., Palmer, J. M., Puig, S., Puig-Butille, J. A., de Snoo, F. A., Stark, M., Tsao, H., Tucker, M. A., Whitaker, L., Yakobson, E., The Lund Melanoma Study Group, , the Melanoma Genetics Consortium (GenoMEL),
(2006). High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL.. Cancer Res.
66: 9818-9828
[Abstract][Full Text]
Ghiorzo, P., Gargiulo, S., Pastorino, L., Nasti, S., Cusano, R., Bruno, W., Gliori, S., Sertoli, M. R., Burroni, A., Savarino, V., Gensini, F., Sestini, R., Queirolo, P., Goldstein, A. M., Scarra, G. B.
(2006). 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
[Abstract][Full Text]
Niendorf, K B, Goggins, W, Yang, G, Tsai, K Y, Shennan, M, Bell, D W, Sober, A J, Hogg, D, Tsao, H
(2006). MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. J. Med. Genet.
43: 501-506
[Abstract][Full Text]
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N., DePinho, R. A.
(2006). Genetics and biology of pancreatic ductal adenocarcinoma.. Genes Dev.
20: 1218-1249
[Abstract][Full Text]
Bardeesy, N., Aguirre, A. J., Chu, G. C., Cheng, K.-h., Lopez, L. V., Hezel, A. F., Feng, B., Brennan, C., Weissleder, R., Mahmood, U., Hanahan, D., Redston, M. S., Chin, L., DePinho, R. A.
(2006). From the Cover: Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl. Acad. Sci. USA
103: 5947-5952
[Abstract][Full Text]
Petersen, G. M., de Andrade, M., Goggins, M., Hruban, R. H., Bondy, M., Korczak, J. F., Gallinger, S., Lynch, H. T., Syngal, S., Rabe, K. G., Seminara, D., Klein, A. P.
(2006). Pancreatic cancer genetic epidemiology consortium.. Cancer Epidemiol. Biomarkers Prev.
15: 704-710
[Abstract][Full Text]
Jimeno, A., Hidalgo, M.
(2006). Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer.. Molecular Cancer Therapeutics
5: 787-796
[Abstract][Full Text]
Florell, S. R., Boucher, K. M., Garibotti, G., Astle, J., Kerber, R., Mineau, G., Wiggins, C., Noyes, R. D., Tsodikov, A., Cannon-Albright, L. A., Zone, J. J., Samlowski, W. E., Leachman, S. A.
(2005). Population-Based Analysis of Prognostic Factors and Survival in Familial Melanoma. JCO
23: 7168-7177
[Abstract][Full Text]
Ocker, M, Neureiter, D, Lueders, M, Zopf, S, Ganslmayer, M, Hahn, E G, Herold, C, Schuppan, D
(2005). Variants of bcl-2 specific siRNA for silencing antiapoptotic bcl-2 in pancreatic cancer. Gut
54: 1298-1308
[Abstract][Full Text]
Marx, S. J., Simonds, W. F.
(2005). Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes. Endocr. Rev.
26: 615-661
[Abstract][Full Text]
Goggins, M.
(2005). Molecular Markers of Early Pancreatic Cancer. JCO
23: 4524-4531
[Abstract][Full Text]
Puig, S., Malvehy, J., Badenas, C., Ruiz, A., Jimenez, D., Cuellar, F., Azon, A., Gonzalez, U., Castel, T., Campoy, A., Herrero, J., Marti, R., Brunet-Vidal, J., Mila, M.
(2005). Role of the CDKN2A Locus in Patients With Multiple Primary Melanomas. JCO
23: 3043-3051
[Abstract][Full Text]
Garber, J. E., Offit, K.
(2005). Hereditary Cancer Predisposition Syndromes. JCO
23: 276-292
[Abstract][Full Text]
Khalid, A, Pal, R, Sasatomi, E, Swalsky, P, Slivka, A, Whitcomb, D, Finkelstein, S
(2004). Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples. Gut
53: 1860-1865
[Abstract][Full Text]
Landi, M T, Goldstein, A M, Tsang, S, Munroe, D, Modi, W, Ter-Minassian, M, Steighner, R, Dean, M, Metheny, N, Staats, B, Agatep, R, Hogg, D, Calista, D
(2004). Genetic susceptibility in familial melanoma from northeastern Italy. J. Med. Genet.
41: 557-566
[Full Text]
Koopmann, J., Goggins, M., Hruban, R. H., Tsao, H., Sober, A. J., Niendorf, K. B.
(2004). Case 7-2004: Hereditary Melanoma and Pancreatic Cancer. NEJM
350: 2623-2624
[Full Text]
Williams, T. M., Lee, H., Cheung, M. W.-C., Cohen, A. W., Razani, B., Iyengar, P., Scherer, P. E., Pestell, R. G., Lisanti, M. P.
(2004). Combined Loss of INK4a and Caveolin-1 Synergistically Enhances Cell Proliferation and Oncogene-induced Tumorigenesis: ROLE OF INK4a/CAV-1 IN MAMMARY EPITHELIAL CELL HYPERPLASIA. J. Biol. Chem.
279: 24745-24756
[Abstract][Full Text]
Goldstein, A M, Struewing, J P, Fraser, M C, Smith, M W, Tucker, M A
(2004). Prospective risk of cancer in CDKN2A germline mutation carriers. J. Med. Genet.
41: 421-424
[Abstract][Full Text]
Oldenburg, R A, de Vos tot Nederveen Cappel, W H, van Puijenbroek, M, van den Ouweland, A, Bakker, E, Griffioen, G, Devilee, P, Cornelisse, C J, Meijers-Heijboer, H, Vasen, H F A, Morreau, H
(2004). Extending the p16-Leiden tumour spectrum by respiratory tract tumours. J. Med. Genet.
41: e31-31
[Full Text]
Hampel, H, Sweet, K, Westman, J A, Offit, K, Eng, C
(2004). Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J. Med. Genet.
41: 81-91
[Abstract][Full Text]
Ghiorzo, P., Pastorino, L., Bonelli, L., Cusano, R., Nicora, A., Zupo, S., Queirolo, P., Sertoli, M., Pugliese, V., Bianchi-Scarra, G.
(2004). INK4/ARF germline alterations in pancreatic cancer patients. Ann Oncol
15: 70-78
[Abstract][Full Text]
Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., DePinho, R. A.
(2003). Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev.
17: 3112-3126
[Abstract][Full Text]
de Vos tot Nederveen Cappel, W. H., Offerhaus, G. J. A., van Puijenbroek, M., Caspers, E., Gruis, N. A., de Snoo, F. A., Lamers, C. B. H. W., Griffioen, G., Bergman, W., Vasen, H. F. A., Morreau, H.
(2003). Pancreatic Carcinoma in Carriers of a Specific 19 Base Pair Deletion of CDKN2A/p16 (p16-Leiden). Clin. Cancer Res.
9: 3598-3605
[Abstract][Full Text]
Parker, J. F., Florell, S. R., Alexander, A., DiSario, J. A., Shami, P. J., Leachman, S. A.
(2003). Pancreatic Carcinoma Surveillance in Patients With Familial Melanoma. Arch Dermatol
139: 1019-1025
[Abstract][Full Text]
Goldstein, A. M., Tucker, M. A.
(2001). Genetic Epidemiology of Cutaneous Melanoma: A Global Perspective. Arch Dermatol
137: 1493-1496
[Full Text]
Kern, S., Hruban, R., Hollingsworth, M. A., Brand, R., Adrian, T. E., Jaffee, E., Tempero, M. A.
(2001). A White Paper: The Product of a Pancreas Cancer Think Tank. Cancer Res.
61: 4923-4932
[Full Text]
Schenk, M., Schwartz, A. G., O'Neal, E., Kinnard, M., Greenson, J. K., Fryzek, J. P., Ying, G. S., Garabrant, D. H.
(2001). Familial Risk of Pancreatic Cancer. JNCI J Natl Cancer Inst
93: 640-644
[Abstract][Full Text]
Sturm, I., Petrowsky, H., Volz, R., Lorenz, M., Radetzki, S., Hillebrand, T., Wolff, G., Hauptmann, S., Dorken, B., Daniel, P. T.
(2001). Analysis of p53/BAX/p16ink4a/CDKN2 in Esophageal Squamous Cell Carcinoma: High BAX and p16ink4a/CDKN2 Identifies Patients With Good Prognosis. JCO
19: 2272-2281
[Abstract][Full Text]
Tersmette, A. C., Petersen, G. M., Offerhaus, G. J. A., Falatko, F. C., Brune, K. A., Goggins, M., Rozenblum, E., Wilentz, R. E., Yeo, C. J., Cameron, J. L., Kern, S. E., Hruban, R. H.
(2001). Increased Risk of Incident Pancreatic Cancer Among First-degree Relatives of Patients with Familial Pancreatic Cancer. Clin. Cancer Res.
7: 738-744
[Abstract][Full Text]
EFTHIMIOU, E, CRNOGORAC-JURCEVIC, T, LEMOINE, N R, BRENTNALL, T A
(2001). Inherited predisposition to pancreatic cancer. Gut
48: 143-147
[Full Text]
Gerdes, B., Ziegler, A., Ramaswamy, A., Wild, A., Langer, P., Bartsch, D. K
(2000). Multiple primaries in pancreatic cancer patients: indicator of a genetic predisposition?. Int J Epidemiol
29: 999-1003
[Abstract][Full Text]
Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M., Masback, A., Westerdahl, J., Olsson, H., Ingvar, C.
(2000). High Frequency of Multiple Melanomas and Breast and Pancreas Carcinomas in CDKN2A Mutation-Positive Melanoma Families. JNCI J Natl Cancer Inst
92: 1260-1266
[Abstract][Full Text]
Hruban, R. H., Goggins, M., Parsons, J., Kern, S. E.
(2000). Progression Model for Pancreatic Cancer. Clin. Cancer Res.
6: 2969-2972
[Full Text]
Goldstein, A. M., Struewing, J. P., Chidambaram, A., Fraser, M. C., Tucker, M. A.
(2000). Genotype-Phenotype Relationships in U.S. Melanoma-Prone Families With CDKN2A and CDK4 Mutations. JNCI J Natl Cancer Inst
92: 1006-1010
[Abstract][Full Text]
Dilworth, D., Liu, L., Stewart, A. K., Berenson, J. R., Lassam, N., Hogg, D.
(2000). Germline CDKN2A mutation implicated in predisposition to multiple myeloma. Blood
95: 1869-1871
[Abstract][Full Text]
Lal, G., Liu, G., Schmocker, B., Kaurah, P., Ozcelik, H., Narod, S. A., Redston, M., Gallinger, S.
(2000). Inherited Predisposition to Pancreatic Adenocarcinoma: Role of Family History and Germ-Line p16, BRCA1, and BRCA2 Mutations. Cancer Res.
60: 409-416
[Abstract][Full Text]
Nielsen, G. P., Stemmer-Rachamimov, A. O., Ino, Y., Moller, M. B., Rosenberg, A. E., Louis, D. N.
(1999). Malignant Transformation of Neurofibromas in Neurofibromatosis 1 Is Associated with CDKN2A/p16 Inactivation. Am. J. Pathol.
155: 1879-1884
[Abstract][Full Text]
Kefford, R. F., Newton Bishop, J. A., Bergman, W., Tucker, M. A.
(1999). Counseling and DNA Testing for Individuals Perceived to Be Genetically Predisposed to Melanoma: A Consensus Statement of the Melanoma Genetics Consortium. JCO
17: 3245-3251
[Full Text]
Yarbrough, W. G., Buckmire, R. A., Bessho, M., Liu, E. T.
(1999). Biologic and Biochemical Analyses of p16INK4a Mutations From Primary Tumors. JNCI J Natl Cancer Inst
91: 1569-1574
[Abstract][Full Text]
Knuutila, S., Aalto, Y., Autio, K., Bjorkqvist, A.-M., El-Rifai, W.'e., Hemmer, S., Huhta, T., Kettunen, E., Kiuru-Kuhlefelt, S., Larramendy, M. L., Lushnikova, T., Monni, O., Pere, H., Tapper, J., Tarkkanen, M., Varis, A., Wasenius, V.-M., Wolf, M., Zhu, Y.
(1999). DNA Copy Number Losses in Human Neoplasms. Am. J. Pathol.
155: 683-694
[Abstract][Full Text]
Orlow, I., LaRue, H., Osman, I., Lacombe, L., Moore, L., Rabbani, F., Meyer, F., Fradet, Y., Cordon-Cardo, C.
(1999). Deletions of the INK4A Gene in Superficial Bladder Tumors : Association with Recurrence. Am. J. Pathol.
155: 105-113
[Abstract][Full Text]
LOWENFELS, A. B., MAISONNEUVE, P.
(1999). Pancreatic Cancer: Development of a Unifying Etiologic Concept. Ann. N. Y. Acad. Sci.
880: 191-200
[Abstract][Full Text]
Huschtscha, L. I., Reddel, R. R.
(1999). p16INK4a and the control of cellular proliferative life span. Carcinogenesis
20: 921-926
[Abstract][Full Text]
Bogardus, S. T. Jr, Concato, J., Feinstein, A. R.
(1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA
281: 1919-1926
[Abstract][Full Text]
Syngal, S., Kaptain, S.
(1999). Case 7-1999- A 50-Year-Old Woman with Severe Diarrhea during Radiation Treatment for Resected Metastatic Melanoma. NEJM
340: 789-796
[Full Text]
Aitken, J., Welch, J., Duffy, D., Milligan, A., Green, A., Martin, N., Hayward, N.
(1999). CDKN2A Variants in a Population-Based Sample of Queensland Families With Melanoma. JNCI J Natl Cancer Inst
91: 446-452
[Abstract][Full Text]
Monzon, J., Liu, L., Brill, H., Goldstein, A. M., Tucker, M. A., From, L., McLaughlin, J., Hogg, D., Lassam, N. J.
(1998). CDKN2A Mutations in Multiple Primary Melanomas. NEJM
338: 879-887
[Abstract][Full Text]
Shapiro, G. I., Edwards, C. D., Ewen, M. E., Rollins, B. J.
(1998). p16INK4A Participates in a G1 Arrest Checkpoint in Response to DNA Damage. Mol. Cell. Biol.
18: 378-387
[Abstract][Full Text]
Pratt, C. B.
(1996). Pediatric Clinical Trials. The Oncologist
1: 169-172
[Abstract][Full Text]
Ciotti, P., Strigini, P., Bianchi-Scarra, G., Wright, F. A., Thomas, R. G., Bergman, W., Gruis, N., Goldstein, A. M., Tucker, M. A., Whelan, A. J., Bartsch, D., Goodfellow, P. J.
(1996). Familial Melanoma and Pancreatic Cancer. NEJM
334: 469-472
[Full Text]
Gostin, L. O.
(1995). Genetic Privacy. J Law Med Ethics
23: 320-330
Previous
