GNAS mutations are associated with mucin production in low-grade appendiceal mucinous neoplasms, villous adenomas, and carcinomas.

Abstract

We read with interest the article by Singhi et al [1] in a recent issue of Human Pathology. The authors reported that a GNASmutation was present in about one-third of both lowgrade and high-grade disseminated appendiceal mucinous neoplasms, and thus, GNAS mutation cannot be used to distinguish between lowand high-grade neoplasms. These tumors are uncommon, and there are limited reported data on the underlying molecular changes in appendiceal mucinous tumors.Wepreviously reported 100%KRASmutations in a cohort of 31 low-grade appendiceal mucinous neoplasms [2]. Using polymerase chain reaction techniques to evaluate the codon 201 region of exon 8 of theGNAS gene, a subsequent evaluation of our tumors has revealed aGNASmutation in 17 (53.1%) of our 32 mucinous neoplasms. The GNAS mutations were closely divided: 9 were R201C, and 8 were the R201H variant. A total of 8 surgical specimens from the 15 (53.3%) tumors with a GNAS mutation demonstrated excess mucin. Five of the 8 had a simultaneous mucinous cystic lesion involving the ovary, interpreted by the surgical pathologist to have originated in the appendix. The other 3 contained omental mucin. Only 2 (13.3%) of the 15 tumors with wild-type GNAS demonstrated mucin beyond the appendiceal lumen, both with peritoneal implants. We also studied 6 villous adenomas of the appendix, and all contained a GNAS mutation. However, of 9 adenocarcinomas of the appendix, only 2 were mutated, and one of these 2 contained copious mucin histologically. Recent large-scale systematic analyses of variants in cancer have revealed numerous potential candidate cancer genes. One such study identified a nonsynonymous base change at codon 201 of the α-subunit of the stimulatory G protein (GNAS) [3]. This protein serves as a ubiquitously expressed signal transducer that transmits hormonal and growth factor signals to effector proteins, particularly activation of the membrane-associated enzyme adenylate cyclase [4]. Mutations that occur at GNAS codon 201 have been shown to constitutively activate the gene and lead to constitutive cAMP signaling. Other in vitro studies suggest that mutant GNAS might play a direct role in prominent mucin production, the hallmark of appendiceal mucinous neoplasms [5]. Our results provide significant clinical evidence for a relationship between GNAS mutations and mucin production in appendiceal tumors, both the low-grade mucinous neoplasms as well as appendiceal villous adenomas and adenocarcinomas. Our results further suggest that it would be of interest to evaluate other mucinous tumors for possible GNAS genetic changes.