TY - JOUR
T1 - Primary colorectal cancers and their subsequent hepatic metastases are genetically different
T2 - Implications for selection of patients for targeted treatment
AU - Vermaat, Joost S.
AU - Nijman, Isaac J.
AU - Koudijs, Marco J.
AU - Gerritse, Frank L.
AU - Scherer, Stefan J.
AU - Mokry, Michal
AU - Roessingh, Wijnand M.
AU - Lansu, Nico
AU - De Bruijn, Ewart
AU - Van Hillegersberg, Richard
AU - Van Diest, Paul J.
AU - Cuppen, Edwin
AU - Voest, Emile E.
PY - 2012/2/1
Y1 - 2012/2/1
N2 - Purpose: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis. Experimental Design: The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material. Results: We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD=69) potentially function-impairing variations were gained in the metastasis and 70 (SD=48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFβ, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation. Conclusion: Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.
AB - Purpose: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis. Experimental Design: The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material. Results: We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD=69) potentially function-impairing variations were gained in the metastasis and 70 (SD=48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFβ, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation. Conclusion: Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.
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U2 - 10.1158/1078-0432.CCR-11-1965
DO - 10.1158/1078-0432.CCR-11-1965
M3 - Article
C2 - 22173549
AN - SCOPUS:84856536814
SN - 1078-0432
VL - 18
SP - 688
EP - 699
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -