title: Novel molecular insights from routine genotyping of colorectal carcinomas.
abstract: Routine tumor genotyping enables identification of concurrent mutations in tumors and reveals low-frequency mutations that may be associated with a particular tumor phenotype. We genotyped 311 colorectal carcinomas (CRCs) for 471 mutation hot spots in 41 cancer-associated genes. At least 1 mutation was present in 239 (77%) of 311 tumors. Two concurrent mutations were identified in 89 (29%) tumors, 3 mutations in 24 (8%), 4 mutations in 6 (2%), and 5 mutations in 1 tumor. KRAS mutations were most frequent and identified in 132 (42%) tumors, followed by APC in 79 (25%) and TP53 in 64 (21%) tumors. Mutations in PIK3CA, BRAF, CTNNB1, and NRAS were identified in 41, 27, 11, and 9 cases, respectively. Rare mutations not typically associated with CRC included AKT1 (4), AKT2 (1), IDH1 (1), KIT (1), MAP2K1 (1), PTEN (2), and GNAS (6). GNAS mutations in CRC correlated with a mucinous phenotype and were present in 20% of all mucinous adenocarcinomas evaluated in this study. Among CRCs with a PIK3CA mutation, 77% showed concurrent mutations in other cancer-associated genes, and 4% of CRC did not neatly fit into either the chromosomal instability pathway or CpG island methylator phenotype/microsatellite instability pathway, suggesting overlapping mutational profile in some tumors. Our findings indicate that routine tumor genotyping is helpful in identifying low-frequency mutations, such as GNAS, that may correlate with a specific morphological phenotype and also reveal multiplicity of concurrent mutations in a significant proportion of CRC that may have significant implications for clinical trial design and personalized therapy.
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Matthew D
authors: MD
authors: Stachler
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Elizabeth
authors: E
authors: Rinehart
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Neal
authors: N
authors: Lindeman
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Robert
authors: R
authors: Odze
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115. Electronic address: asrivastava@partners.org.
authors: Amitabh
authors: A
authors: Srivastava
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
keywords: Adenocarcinoma; Colon; GNAS; Genotyping; Mutations