Correlation between DPYD gene variation and KRAS wild type status in colorectal cancer.
OBJECTIVE
Failure and side effects of combined cytotoxic therapy are challenges in the treatment of metastatic colorectal cancer (CRC). DPYD gene variations can potentially predict toxicity to 5-fluorouracil (FU)-based therapy and KRAS-, NRAS-, BRAF-, PIK3CA-wild type status is a known prerequisite for epidermal growth factor receptor (EGFR) inhibitor therapy. This study was performed to search for a possible link between these therapeutic markers.


METHODS
The DPYD gene variations c.496A>G, c.1679T>G, c.2846A>T and KRAS/NRAS/BRAF/PIK3CA mutational status were determined in non-neoplastic, primary CRC and metastatic CRC tissue from 115 patients.


RESULTS
The polymorphism c.496A>G was the DPYD gene variant with the highest detection rate (12.9%), occurred predominantly in females (86.7%, p=0.0044) and was exclusively seen in KRAS wild type primary CRC (15/65 (23.1%) vs 0/51 (0%) in KRAS-mutated primary CRC, respectively, p=0.0001).


CONCLUSIONS
This genetic profile could define a patient group requiring alternative combined therapeutic approaches. Global testing of large patient cohorts is necessary to prove this concept.
Department of Pathology, Southern Hospital Trust, Kristiansand, Norway.
Britta
B
Kleist
Institute of Legal Medicine, University Hospital Essen, Essen, Germany.
Marcel
M
Kempa
Institute of Legal Medicine, University Hospital Essen, Essen, Germany.
Thuja
T
Meurer
Institute of Legal Medicine, University Hospital Essen, Essen, Germany.
Micaela
M
Poetsch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D042943:Dihydrouracil Dehydrogenase (NADP); C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D005472:Fluorouracil
CANCER GENETICS; COLORECTAL CANCER; DIAGNOSTICS