OR29-1 Mutations in the DNA Mismatch Repair Genes Predispose to Adrenocortical Carcinoma

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR29-Adrenal Tumors & Pheochromocytoma
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 134 (Moscone Center)
Tobias Else*1, Jessica N Everett1, Shanna L Gustafson1, Stephen B Gruber2, Gary D Hammer1, Elena M Stoffel1 and Victoria M Raymond1
1University of Michigan, Ann Arbor, MI, 2University of Southern California, Los Angeles, CA
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and pediatric ACC is strongly associated with germline mutations of TP53, however the association of adult onset ACC with inherited cancer predisposition syndromes has not been well described. Lynch syndrome, caused by mutations in the DNA mismatch repair genes (MMR) is the most common colon cancer predisposition syndrome which dramatically increases the risk for several cancers. This study aimed to evaluate Lynch syndrome (LS) as a condition predisposing to ACC.  

Patients were recruited in an Endocrine Oncology Clinic. 114 patients with confirmed ACC evaluated in the Clinic between December 2009 and October 2011 were prospectively offered genetic counseling, construction of a four generation pedigree and clinical genetics risk assessment.  All probands with known mismatch repair (MMR) gene mutations recorded in the University of Michigan Cancer Genetics Registry (CGR) were evaluated for the presence of ACC.

Of the 114 patients 94 met with a genetic counselor (82.5%). The average age at ACC diagnosis was 45.8 years (3 to 82 years) with 98% diagnosed over age 18. Three (3.2%) individuals had family histories suggestive of LS and all 3 families were found to have MMR gene mutations in MSH2 (p.R711X ), MSH6 (p.S714C), MLH1 (p.L749P).  Review of an additional 140 MMR gene positive probands in the CGR identified two patients with MSH2 mutations (IVS5+3A>T; c.792+1G>A) diagnosed with ACC. Four tumors were available for further analysis. Immunohistochemistry for MSH2, MSH6, PMS2 and MLH1 were in accordance with the mutation in 3 of the 4 cases. All tumors were microsatellite stable.

This prospective series of patients with ACC demonstrated the prevalence of Lynch Syndrome to be 3.2% which is comparable to the prevalence of Lynch Syndrome among cases of colorectal and endometrial cancer (1-5%). Patients with ACC in the setting of a personal or family history of LS tumors should be strongly considered for genetic testing. Furthermore, immunohistochemistry of ACC as a screening tool for LS may identify patients that may benefit from genetic testing.

Disclosure: GDH: Consultant, orphagen, Founder, Atterocor, Consultant, Embera, Advisory Group Member, Embera, Consultant, HRA Pharma, Consultant, Corcept, Consultant, Isis, Advisory Group Member, orphagen, Consultant, OSI-Astella. Nothing to Disclose: TE, JNE, SLG, SBG, EMS, VMR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: T.E. NIH T32-DK007245
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