Expression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma.
Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5 to 8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared with conventional carcinoma (CC) but, to date, only one previous study has analyzed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an overexpression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by quantitative real-time PCR (qPCR) and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity = 100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signaling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes.
Department of Pathology, Santa Lucía General University Hospital, Cartagena, Spain. pablo.conesa@carm.es
Pablo
P
Conesa-Zamora
José
J
García-Solano
Francisco
F
García-García
María Del Carmen
Mdel C
Turpin
Javier
J
Trujillo-Santos
Daniel
D
Torres-Moreno
Isabel
I
Oviedo-Ramírez
Rosa
R
Carbonell-Muñoz
Encarnación
E
Muñoz-Delgado
Edith
E
Rodriguez-Braun
Ana
A
Conesa
Miguel
M
Pérez-Guillermo
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D051597:Hippocalcin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D059467:Transcriptome
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C502658:FSCN1 protein, human; C496691:HPCA protein, human; D008840:Microfilament Proteins; C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D051597:Hippocalcin