Specific genomic aberrations in primary colorectal cancer are associated with liver metastases.
BACKGROUND
Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases.


METHODS
Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25).A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM).


RESULTS
Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations.


CONCLUSIONS
Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management.
Division of Experimental Therapy, Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Sjoerd C
SC
Bruin
Christiaan
C
Klijn
Gerrit-Jan
GJ
Liefers
Linde M
LM
Braaf
Simon A
SA
Joosse
Eric H
EH
van Beers
Victor J
VJ
Verwaal
Hans
H
Morreau
Lodewyk F
LF
Wessels
Marie-Louise F
ML
van Velthuysen
Rob A E M
RA
Tollenaar
Laura J
LJ
Van't Veer
D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D002869:Chromosome Aberrations; D002890:Chromosomes, Human, Pair 20; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D055028:Comparative Genomic Hybridization; D030541:Databases, Genetic; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009426:Netherlands; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding; D010641:Phenotype; D011237:Predictive Value of Tests; D016019:Survival Analysis; D013997:Time Factors; D016707:Tissue Fixation / Q000379:methods; D016896:Treatment Outcome
D005404:Fixatives; D005557:Formaldehyde