A correlation of the endoscopic characteristics of colonic laterally spreading tumours with genetic alterations.
OBJECTIVE
Laterally spreading tumours (LSTs) are a heterogeneous group of adenomas that are emerging as important precursors of colorectal cancer and in which the risk for cancer is related to their endoscopically definable morphology. It is currently unclear whether different molecular alterations determine their morphologies. We aimed to assess this relationship in LSTs using strict morphological classifications.


METHODS
We characterized 135 sessile adenomatous lesions (≥ 20 mm) according to histopathology and the Paris classification. We investigated key molecular changes commonly found in colorectal neoplasms, namely mutation of KRAS, BRAF, APC and CTNNB1 and microsatellite instability, and determined their relationship with morphology.


RESULTS
The Paris classification revealed a heterogeneous cohort comprising Is/IIa+Is (41.5%), IIa/IIb (53.3%) and IIc/IIa+IIc (5.2%) lesions. Histopathological analysis showed that 19 (14.1%) of these were sessile serrated adenomas. Here, we defined a group of 58 lesions that showed either Paris IIa or IIb morphology with no serrated histopathology. These 'classical LSTs' showed the following molecular characteristics: microsatellite instability 0/56 (0%), APC mutation 29/30 (96.7%), CTNNB1 mutation 2/55 (3.6%), KRAS mutation 24/55 (43.6%) and BRAF mutation 2/55 (3.6%). Separation of lesions according to surface morphology showed that KRAS mutations occurred much more frequently in granular (56.4%, 22/39) than in nongranular LSTs (12.5%, 1/16, P=0.004).


CONCLUSIONS
The microsatellite instable pathway is not important in the development of LSTs, which are instead likely to develop along a divergent chromosomal instability pathway. We demonstrate the biological significance of endoscopic findings by showing that the morphological characteristics of LSTs are underpinned by distinctive molecular profiles.
Department of Gastroenterology, Westmead Hospital, Sydney, New South Wales, Australia.
Andrew J
AJ
Metz
Michael J
MJ
Bourke
Alan
A
Moss
Ashraf
A
Dower
Peter
P
Zarzour
Nicholas J
NJ
Hawkins
Robyn L
RL
Ward
Luke B
LB
Hesson
D000236:Adenoma / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016009:Chi-Square Distribution; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D003113:Colonoscopy; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009517:New South Wales; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051176:beta Catenin / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins