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Endocrine Care: A. F. Daly, M.-L. Jaffrain-Rea, A. Ciccarelli, H. Valdes-Socin, V. Rohmer, G. Tamburrano, C. Borson-Chazot, B. Estour, E. Ciccarelli, T. Brue, P. Ferolla, P. Emy, A. Colao, E. De Menis, P. Lecomte, F. Penfornis, B. Delemer, J. Bertherat, J. L. Wémeau, W. De Herder, F. Archambeaud, A. Stevenaert, A. Calender, A. Murat, F. Cavagnini, and A. Beckers Clinical Characterization of Familial Isolated Pituitary Adenomas J Clin Endocrinol Metab 2006; 91: 3316-3323 [Abstract] [Full text] [PDF]

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PITUITARY ADENOMA PREDISPOSITION

Kari Hemminki, Asta Försti, Jianguang Ji   (5 July 2006)

PITUITARY ADENOMA PREDISPOSITION 5 July 2006
Kari Hemminki, Professor Division of Molecular Genetic Epidemiology, German Cancer Research Center, Asta Försti, Jianguang Ji Send letter to journal: Re: PITUITARY ADENOMA PREDISPOSITION K.Hemminki{at}dkfz.de Kari Hemminki, et al.	Two important papers have recently been published on pituitary adenomas identifying novel familial clustering (1, 2). Daly et al. (1) described a respectable multinational series of 64 families with two or more affected individuals with pituitary adenoma, characterized in respect to the clinical and hormonal status. Multiple endocrine neoplasia 1 and Carney complex were excluded. The size of the covered population was not given; however, 22 clinics from four European countries participated. A comparison group of sporadic tumors (N=2600) was collected from two of the participating clinics, giving an indication of the very large population covered. Vierimaa et al identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in patients diagnosed with pituitary adenoma (2). The tumors were oversecreting prolactin or growth hormone (GH) and the rare index phenotype in the patients was excessive growth, diagnosed as acromegaly or gigantism. Many patients lacked a strong family history, suggesting that AIP is a low- penetrance tumor susceptibility gene. Because of the low penetrance, inherited predisposition to AIP may be difficult to detect in families in a clinical setting. We wanted to examine whether evidence for heritable effects on GH- producing pituitary adenomas could be found among 10.6 million individuals included in the nation-wide Swedish Family-Cancer Database, covering malignancies from years 1958 to 2002 (3). Only some 25-30% of the surgically removed pituitary adenomas secrete GH (4); the Database contains no details on the hormone secreting properties of the tumors. Age -standardized incidence ratios (SIRs) were calculated for pituitary adenomas in the 0 to 70 year old offspring generation according to occurrence of these tumors in their parents; SIRs were also calculated for second primary tumors in pituitary adenoma patients (3). Among a total of 3239 pituitary tumor patients, only 3 concordant parent-offspring pairs were identified, all diagnosed before age 50 years (SIR 2.3, 95% confidence intervals (CIs) 0.4-7.0). The proportion of familial cases may not be substantially smaller than in the above European study, considering that the latter was clinically based and could identify family members back in history (1). According to The Family-Cancer Database, the risk for a second pituitary tumor after an initial pituitary tumor was 15.0 (8.2- 25.2, N=14). Colorectal cancer is the only cancer type considered to be increased in acromegaly patients (5). The risk of pituitary adenoma was marginally increased in individuals whose parents (SIR 1.2, 1.0-1.5, N=90) or siblings (SIR 1.6, 0.9-2.7, N=15) were diagnosed with colorectal cancer. Pituitary tumors were also in excess in patients first diagnosed with colorectal cancer (SIR 2.2, 1.5-3.1, N=30). Although we cannot definitely exclude contribution by other syndromes with a pituitary involvement, such as multiple endocrine neoplasia 1 and Carney complex (4), the results were identical when the analyses were repeated after the removal of all families presenting with any endocrine tumors other than pituitary adenomas. These data provide population-level support to the notion that pituitary adenomas constitute an inherited cancer predisposition. Acknowledgments: The Family-Cancer Database was created by linking registries maintained by Statistics Sweden and the Swedish Cancer Register, and supported by the Deutsche Krebshilfe, the Swedish Cancer Society, the Swedish Council for Working Life and Social Research and the EU, LSHC-LT-2004-503465. References 1. Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin, V. Rohmer, G. Tamburrano, C. Borson-Chazot, B. Estour, E. Ciccarelli, T. Brue, P. Ferolla, P. Emy, A. Colao, E. De Menis, P. Lecomte, F. Penfornis, B. Delemer, J. Bertherat, J. L. Wémeau, W. De Herder, F. Archambeaud, A. Stevenaert, A. Calender, A. Murat, F. Cavagnini, and A. Beckers. 2006 Clinical Characterization of Familial Isolated Pituitary Adenomas. J Clin Endocrinol Metab epub ahead of print, DOI 10.1210/jc.2005-2671 2. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM L, Salmela PI, Paschke R, Gündogdu S, De Menis E, Mäkinen MJ, Launonen V, Karhu A, Aaltonen LA. 2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312:1228-1230 3. Hemminki K, Li X, Plna K, Granström C, Vaittinen P. 2001 The nation-wide Swedish Family-Cancer Database: updated structure and familial rates. Acta Oncol 40:772-777 4. DeLellis R, Lloyd R, Heitz P, Eng C, eds. 2004 Pathology and Genetics of Tumours of Endocrine Origin. IARC Press, Lyon, France 5. Jenkins PJ, Mukherjee A, Shalet SM 2006 Does growth hormone cause cancer? Clin Endocrinol (Oxf) 64:115-121