Colorectal serrated adenocarcinoma shows a different profile of oncogene mutations, MSI status and DNA repair protein expression compared to conventional and sporadic MSI‐H carcinomas

Abstract

Molecular characterization has been extensively studied in serrated polyps but very little is known in serrated adenocarcinomas (SACs). We analyzed the incidence of KRAS, BRAF and PIK3CA mutations, microsatellite instability (MSI) status and loss of the DNA repair proteins MLH1, MSH2, MSH6 and MGMT in a series of 89 SAC, 81 matched conventional carcinomas (CC) and 13 sporadic colorectal cancer showing histological and molecular features of high-level MSI (sMSI-H). Our results demonstrate that KRAS are more prevalent than BRAF mutations in SAC (42.7% vs. 25.8%; p 5 0.011) being the KRAS-mutated cases even more abundant in SAC displaying adjacent serrated adenomas (51%). G12D and E545K are the most common KRAS and PIK3CA mutations found in SAC, respectively. SAC show higher frequency of MGMT loss compared to CC (50.6% vs. 25.3%; p 5 0.001) especially in distal colon/rectum (60.0% vs. 21.6%; p 5 0.0009). SAC differ from sMSI-H in terms of KRAS and BRAF mutation prevalence, MSI status and MLH1 expression (p 5 0.0003, p < 0.0001, p < 0.0001, p < 0.001, respectively). SACs are more often KRAS-mutated and microsatellite stable and display different molecular and immunohistochemical characteristics compared to CC and sMSI-H.KRAS and BRAF are key mediators in the RAS-mitogen activated protein kinase (MAPK) signalling pathway of transduction signals and several components of this route are regarded as promising targets of anticancer drugs. 1,2 Activating KRAS mutations are present in about 37-50% of all colorectal cancers (CRC) 3,4 and most (90%) are found in codons 12 and 13 of exon 1. 5 On the other hand, BRAF activating mutations have been identified in about 13% of CRC 6 and a single activating point mutation at the V600E locus accounts for 80% of BRAF mutations in CRC. 7 This mutation has high sensitivity and specificity for the serrated polyp pathway and is rarely, if ever, found in the conventional adenoma-carcinoma sequence 8,9 and is strongly associated with sporadic microsatellite instability (sMSI) and DNA methylation abnormalities. 8,10 However, it has been recently demonstrated that KRAS mutations are also frequent in the serrated polyp pathway. 11 The PIK3K/AKT pathway regulates various cellular processes including proliferation, growth, apoptosis and cytoskeletal rearrangement 12 and is considered to play an important role in colorectal carcinogenesis either through RAS mutation or

PIK3CA mutations are frequently observed in BRCAX but not BRCA2-associated male breast cancer

“…The E547K mutation itself is found in the highly conserved helical domain of PIK3CA and possibly confers increased catalytic activity. The mutation is not unique to breast cancer, and has also been reported previously in one colorectal adenocarcinoma [45] and in seven neuroendocrine tumours of the lung [46] lending support for a true pathogenic mutation. Targeted sequencing of further MBC, and in particular non-BRCA2 tumours, may help determine a more accurate incidence and potential relevance of this uncommon mutation.…”

Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis

“…Thus, many of the invasive carcinomas in our series were diagnosed as serrated adenocarcinomas. Most serrated adenocarcinomas examined previously were microsatellite-stable or had low levels of microsatellite instability with KRAS or BRAF mutation, 14,23 which are molecular features similar to those of the traditional serrated adenomas with cytologic dysplasia studied here. Traditional serrated adenoma is therefore likely to be a precursor of serrated adenocarcinoma.…”

“…Recent data have suggested the existence of a second serrated pathway to colon carcinoma: the cancers in this subset of colon cancer are often microsatellite-stable or have low levels of microsatellite instability with either BRAF or KRAS mutation. 5,9,[14][15][16] Some of the cancers in the second subset of colon cancers meet the morphological criteria of serrated adenocarcinoma, and serrated adenocarcinoma has been reported to develop from traditional serrated adenoma. 14 Thus, traditional serrated adenoma may represent a distinct serrated precursor in colorectal carcinogenesis with a unique molecular pathogenesis.…”

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival

“…In contrast with conventional colorectal adenocarcinoma resulting from a conventional adenoma-carcinoma sequence, SACs have a higher frequency of BRAF or KRAS mutations and higher levels of CIMP [15, 21–23]. The cause or mechanism of CIMP in CRC is not yet known.…”

“…CIMP and BRAF mutations are associated with serrated CRC development, and these mutations occur frequently in MACs and SACs [7, 8, 10, 11, 15, 21–23, 26]. MACs and SACs also share other features, including right-side colon location and frequent mucin production.…”