K-ras 146, N-ras 12/13, and N-ras 61 mutations in Quasar1 stage II/III colorectal cancers occur in 6% of cases.  A small but important group?


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Katie Southward1, Morag Taylor1, Kelly Handley2, Laura Magill2, Phil Chambers1, Claire Beaumont1, Susan Richman1, Matt Seymour3, David Kerr4, Richard Gray2, Phil Quirke1
1Leeds Institute of Molecular Medicine, Leeds, UK, 2Birmingham Clinical Trials Unit, Birmingham, UK, 3Cancer Research UK Clinical Centre, Leeds, UK, 4Department of Clinical Pharmacology, Oxford, UK

Background

Activating mutations in the Kirsten ras gene are known to be associated with failure to respond to anti-EGFr therapy in advanced and poor prognosis in stage II and IV colorectal cancer. Other members of the Ras family are known to be mutated in CRC and such tumours may also not benefit from anti-EGFr therapy but the frequency and clinical relevance of these mutations is unknown.

Method

We have assessed K-ras codon 146 and N-ras codons 12,13 and 61 mutation as potential additional markers of poor prognosis in 1596 cases (92% stageII) from the Quasar-I clinical trial by pyrosequencing.

Results

K-ras 12/13 or 61 mutations were detected in 542 (34%) of cases. Of the 1054 tumours wildtype for K-ras 12/13 and K-ras 61, 52 (4.9%) had a K-ras 146 mutation, 25 (2.4%) a N-ras 12/13 mutation and 15 (1.4%) a N-ras 61 mutation. In addition, 2 cases had a mutation at K-ras 12/13 and K-ras 146, 2 cases a mutation at K-ras 12/13 and N-ras 12/13 and 1 a mutation at K-ras 61 and N-ras 61 (0.3% of total).  No K-ras 146 or N-ras mutated tumour carried a B-raf codon 600 mutation. The mutations in this study occur with equal frequency throughout the large bowel.

Conclusion

K-ras 146 and N-ras 12/13 and 61 mutations occurred in 5.8% of these mainly stage II cancers, double mutations are rare – so these would not be picked up by current standard ras mutation testing - and like K-ras 12/13/61 they do not occur with B-raf mutations. Their existence should be considered when selecting patients for anti EGFr therapy in trials such as Foxtrot.