APC mutation and tumour budding in colorectal cancer

Abstract

Aim: To determine the frequency of tumour budding and somatic APC mutation in a series of colorectal cancers stratified according to DNA microsatellite instability (MSI) status.

Material/methods: Ninety five colorectal cancers were genotyped for APC mutation in the mutation cluster region (exon 15) and scored for the presence of tumour budding at the invasive margin in haematoxylin and eosin stained sections. A subset was immunostained for beta catenin and p16.

Results: The frequency of both somatic APC mutation and tumour budding increased pari passu in cancers stratified as sporadic MSI high (MSI-H), hereditary non-polyposis colorectal cancer (HNPCC), MSI low (MSI-L), and microsatellite stable (MSS). Both budding and APC mutation were significantly less frequent in sporadic MSI-H cancers than in MSI-L or MSS cancers. Tumour buds were characterised by increased immunostaining for both beta catenin and p16.

Conclusion: Tumour budding is associated with an adverse prognosis. The lack of budding in MSI-H colorectal cancer may account for the improved prognosis of this subset and may be explained by an intact WNT signalling pathway and/or inactivated p16(INK4a).

Figure 1

Tumour budding demonstrated by small cell clusters at the invasive margin of a colorectal cancer (haematoxylin and eosin; original magnification, ×40).

Figure 2

Extensive cytoplasmic and nuclear immunostaining for β catenin in tumour buds (avidin–biotin complex technique).

Figure 3

Tumour buds showing cytoplasmic expression of p16 (avidin–biotin complex technique).

Figure 4

Dysregulated p16 binds cyclin dependent kinase 4 (cdk4), which results in cytoplasmic sequestration of cdk4. Binding between nuclear cyclin D1 and cdk2 results in an inert complex but serves to compete with the binding of cdk2 to cyclins A and E. This may explain why there is increased expression of nuclear cyclin D1 in tumour buds whereas proliferation is decreased.