Adrenocortical Carcinoma Is a Lynch Syndrome–Associated Cancer

Abstract

Purpose Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC. Patients and Methods One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency. Results Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene–positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status. Conclusion The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

“…In parallel with recent advances in molecular genetics, immunohistochemistry has been shown to detect various types of molecular alterations, that is, BRAF V600E mutation in papillary thyroid carcinomas, 48 PTEN mutations in various neoplastic thyroid lesions, 49 CTNNB1 mutations in cribriform-morular variant of papillary thyroid carcinoma, undifferentiated carcinomas of the thyroid gland and adrenocortical carcinomas, 48,50,51 TP53 mutations as well as mutations in mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2 in adrenocortical carcinomas, [51][52][53] HRPT2 mutations in parathyroid carcinomas and hyperparathyroidism-jaw tumor syndrome-related adenomas, 48,54 PRKAR1A mutations in Carney complex-associated tumors, [55][56][57] and SDH-, FH-as well as MAX deleterious-mutations in pheochromocytomas/paragangliomas. 8,10,11,58,59 Loss of SDHB protein expression is seen in pheochromocytomas/paragangliomas either harboring a mutation in any of the SDH genes or with somatic hypermethylation of the SDHC promoter region, 42 whereas loss of both SDHB and SDHA immunoreactivity is demonstrated only in the context of an SDHA mutation.…”

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

“…Most ACCs occur sporadically, but ACCs can also be associated with various genetic syndromes, e.g. Li Fraumeni syndrome (Kleihues et al 1997, Birch et al 2001, Gonzalez et al 2009), Beckwith-Wiedemann syndrome (BWS) (Wiedemann 1983, Steenman et al 2000, Lapunzina 2005, multiple endocrine neoplasia type 1 (MEN1) (Waldmann et al 2007, Gatta-Cherifi et al 2012 and Lynch syndrome (Medina-Arana et al 2011, Karamurzin et al 2012, Raymond et al 2013. To a lesser extent, ACC can be associated with familial adenomatous polyposis , neurofibromatosis type 1 (Wagner et al 2005) and Werner syndrome (Takazawa et al 2004).…”

Adrenocortical Growth and Cancer

“…Karamurzin et al reported four cases of ACC in patients with Lynch syndrome (167) and recently, Raymond et al studied a large cohort of ACC (n = 94) and identified three patients (3.2%) with a family history suggestive of LS (270). Mutations in the MMR gene were found in the three families.…”