Comparative genomic analysis of primary versus metastatic colorectal carcinomas.
OBJECTIVE
To compare the mutational and copy number profiles of primary and metastatic colorectal carcinomas (CRCs) using both unpaired and paired samples derived from primary and metastatic disease sites.


METHODS
We performed a multiplatform genomic analysis of 736 fresh frozen CRC tumors from 613 patients. The cohort included 84 patients in whom tumor tissue from both primary and metastatic sites was available and 31 patients with pairs of metastases. Tumors were analyzed for mutations in the KRAS, NRAS, BRAF, PIK3CA, and TP53 genes, with discordant results between paired samples further investigated by analyzing formalin-fixed, paraffin-embedded tissue and/or by 454 sequencing. Copy number aberrations in primary tumors and matched metastases were analyzed by comparative genomic hybridization (CGH).


RESULTS
TP53 mutations were more frequent in metastatic versus primary tumors (53.1% v 30.3%, respectively; P < .001), whereas BRAF mutations were significantly less frequent (1.9% v 7.7%, respectively; P = .01). The mutational status of the matched pairs was highly concordant (> 90% concordance for all five genes). Clonality analysis of array CGH data suggested that multiple CRC primary tumors or treatment-associated effects were likely etiologies for mutational and/or copy number profile differences between primary tumors and metastases.


CONCLUSIONS
For determining RAS, BRAF, and PIK3CA mutational status, genotyping of the primary CRC is sufficient for most patients. Biopsy of a metastatic site should be considered in patients with a history of multiple primary carcinomas and in the case of TP53 for patients who have undergone interval treatment with radiation or cytotoxic chemotherapies.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Efsevia
E
Vakiani
Manickam
M
Janakiraman
Ronglai
R
Shen
Rileen
R
Sinha
Zhaoshi
Z
Zeng
Jinru
J
Shia
Andrea
A
Cercek
Nancy
N
Kemeny
Michael
M
D'Angelica
Agnes
A
Viale
Adriana
A
Heguy
Philip
P
Paty
Timothy A
TA
Chan
Leonard B
LB
Saltz
Martin
M
Weiser
David B
DB
Solit
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000556:secondary*; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D008297:Male; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf