Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers.
OBJECTIVE
Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR-targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence.


METHODS
The study population comprised 1,492 retrospectively collected stages I-IV colorectal cancer specimens. Tissue was obtained between 2000 and 2010 at a single hospital. We analyzed 61 hot spots using MALDI-TOF mass spectrometry for nucleic acid analysis.


RESULTS
Mutations were found in the RAS pathway in 47.3% of patients and in the PI3K pathway in 14.3% of patients, with 9.2% of patients carrying mutations in both pathways. Both the RAS and PI3K pathway mutations were significantly associated with proximal tumors, mucinous tumors, and microsatellite instability. Tumors carrying a RAS pathway mutation exhibited a higher frequency of lung and peritoneal metastasis than did tumors with a wild-type gene (P = 0.025 and 0.009, respectively). NRAS gene mutation was significantly associated with lung metastasis (P = 0.001).


CONCLUSIONS
Somatic mutations in the RAS pathway of the primary tumor in colorectal cancer can influence patterns of metastasis and recurrence.
Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Yuan-Tzu
YT
Lan
Lin
L
Jen-Kou
Chien-Hsing
CH
Lin
Shung-Haur
SH
Yang
Chun-Chi
CC
Lin
Huann-Sheng
HS
Wang
Wei-Shone
WS
Chen
Tzu-Chen
TC
Lin
Jeng-Kai
JK
Jiang
Shih-Ching
SC
Chang
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins
colorectal cancer; epidermal growth factor receptor; metastasis; signaling pathway