The molecular epidemiology of KRAS and NRAS mutations in 2,761 colorectal adenocarcinomas


Year:

Session type:

Theme:

Matthew Evans1,Brendan O'Sullivan1,Frances Hughes1,Claire Swift1,Reena Dessi1,Tina Mullis1,Matthew Smith1,Philippe Taniere1
1Queen Elizabeth Hospital Birmingham

Abstract

Background

RAS testing is mandatory prior to anti-EGFR1 monoclonal antibody therapy in colorectal adenocarcinoma and is a strong negative predictive marker for response to the drug.

Between 2008 and 2013 our testing was restricted to commonly-mutated codons 12 and 13 of KRAS; however since then we have extended testing to rarely-mutated codons within KRAS and to NRAS.

We present here the spectrum of mutations in these two genes in our molecular pathology diagnostic service, in relation to patient age and sex.

Method

All tumours tested for KRAS and NRAS mutation in the last 36 months were retrieved from our database (2,761 specimens). Tumours are tested for RAS mutation by pyrosequencing (therascreen KRAS and NRAS Pyro Kits); the following codons are analysed: KRAS: 12, 13, 61 and 146; NRAS: 12, 13 and 61.

Information was collected about patient age and sex, and type of mutation.

Results

42.4% of specimens harboured a RAS mutation: 

Codon

12

13

61

146

KRAS mutations (%)

725

70.5%

185

18.0%

50

4.9%

69

6.7%

NRAS mutations (%)

25

23.1%

8

7.4%

75

69.4%

-

There was no significant mutation rate and patient age or sex. Mutations were more common in the right than left colon (51.1% vs 41.7%, p < 0.001), this difference driven by mutations in caecal cancers (65.6%).

There was no significant association between the location of the mutation and patient sex, but all mutations in patients aged younger than 30 years were in codon 12. Overall, transitions were slightly commoner than transversions; there was no significant association between the transition/transversion ratio and patient sex, patient age or tumour location.

Conclusion

Our data show that the extra KRAS and NRAS codons together represent 19.3% of all RAS mutations detected. We conclude that this high proportion justifies mandatory testing of specimens for these less common mutations.