Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms

• Published in: British journal of cancer Vol. 108; no. 4; pp. 951 - 958
• Main Authors: Nishikawa, G, Sekine, S, Ogawa, R, Matsubara, A, Mori, T, Taniguchi, H, Kushima, R, Hiraoka, N, Tsuta, K, Tsuda, H, Kanai, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-03-2013; Nature Publishing Group
• Subjects: 631/208/737; 692/420/2489/144/68; 692/699/67/1504/1885; Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Animals; Appendiceal Neoplasms - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromogranins; Classification; Colorectal cancer; Drug Resistance; Epidemiology; Female; Genes, ras; GTP-Binding Protein alpha Subunits, Gs - genetics; Humans; Male; Medical prognosis; Medical research; Medical sciences; Mice; Mice, Nude; Middle Aged; Molecular Diagnostics; Molecular Medicine; Mutation; Neoplasm Transplantation; Oncology; Ovaries; Pancreas; Transplantation, Heterologous; Tumors; Japan; low-grade mucinous appendiceal neoplasm; K ras Gene; Cancerology; Low malignancy; C-Onc gene; GNAS; Frequency; Genetics; Tumor; KRAS; Mutation; Protooncogene; Low grade
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.47

Background:
The molecular basis for the development of appendiceal mucinous tumours, which can be a cause of pseudomyxoma peritonei, remains largely unknown.
Methods:
Thirty-five appendiceal mucinous neoplasms were analysed for
GNAS
and
KRAS
mutations. A functional analysis of mutant
GNAS
was performed using a colorectal cancer cell line.
Results:
A mutational analysis identified activating
GNAS
mutations in 16 of 32 low-grade appendiceal mucinous neoplasms (LAMNs) but in none of three mucinous adenocarcinomas (MACs).
KRAS
mutations were found in 30 LAMNs and in all MACs. We additionally analysed a total of 186 extra-appendiceal mucinous tumours and found that
GNAS
mutations were highly prevalent in intraductal papillary mucinous tumours of the pancreas (88%) but were rare or absent in mucinous tumours of the colorectum, ovary, lung and breast (0–9%). The prevalence of
KRAS
mutations was quite variable among the tumours. The introduction of the mutant
GNAS
into a colorectal cancer cell line markedly induced
MUC2
and
MUC5AC
expression, but did not promote cell growth either
in vitro
or
in vivo
.
Conclusion:
Activating
GNAS
mutations are a frequent and characteristic genetic abnormality of LAMN. Mutant
GNAS
might play a direct role in the prominent mucin production that is a hallmark of LAMN.