Roel Bogie

General discussion

The more frequently present flat appearance of PCCRCs in comparison to prevalent CRCs has been discussed above, as this was one of the arguments for the hypothesis that non-polypoid neoplasms contribute to etiology of PCCRCs. The molecular profile of PCCRCs that we have determined, supported this assumption. LSTs also have other specific molecular features. Multiple studies compared molecular features between granular and non-granular LSTs. Non-granular LSTs have less often KRAS gene mutations than granular LSTs. 66-69 In particular KRAS gene mutations may be associated with LST-G in the proximal colon. 70 APC gene mutations were less common in LST-NG, 71 but were overall more often present in LSTs. 72 LST-G and polypoid CRNs appeared to have similar molecular findings in several studies, 66, 71 so perhaps LST-NG have more molecular features in common with non-polypoid neoplasms. Overall, TP53 and BRAF gene mutations and MSI were uncommon in LSTs. 71 High-methylation phenotypes were also uncommon, 73 so LSTs do not match the frequently seen molecular features of PCCRCs as discussed in Chapter 10 . Another study combined LST genetics, epigenetics and transcriptomics and showed that LSTs had a number of mutations comparable to microsatellite stable CRC. 74 In that study, APC, KRAS, SOX9 and BRAF were often found to be mutated in LSTs, but these mutations were identified as early clonal events. ANO5, NRXN1 and SLITRK1 genes were also often mutated and methylated, which is a new finding. The axonal guidance system was affected in comparison to normal mucosa, which could be the explanation why LSTs have a lateral instead of luminal growth pattern. All by all, it is very likely that LSTs are precursors of CRCs according to the chromosomal instability pathway. Thus, it is possible that LSTs are precursor lesions of PCCRCs that develop through the chromosomal instability pathway and that sessile serrated lesions may cause PCCRCs through MSI and hypermethylation pathways.

Neoplasm factors

Patient factors

Subtle endoscopic apearance

Occurence of sessile serrated lesions

LST

Difficult endoscopic detection

Frequent metachronous neoplasms

LST

Proximal location

Faster neoplasm growth

Multiple synchronous neoplasms

PCCRC

Inadequate bowel cleansing

Non-adherence to surveillance

12

Endoscopist factors

Insufficient training

Incomplete colonoscopies

Figure 12.2: Overviewof the factors contributing to PCCRC occurence and the factors associatedwith LSTs.

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