Colorectal cancer with and without microsatellite instability involves different genes

Salahshor, Sima; Kressner, Ulf; Påhlman, Lars; Glimelius, Bengt; Lindmark, Gunilla; Lindblom, Annika

doi:10.1002/(sici)1098-2264(199911)26:3<247::aid-gcc9>3.0.co;2-h

Cited by 121 publications

(65 citation statements)

References 32 publications

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“…24 Alternative pathways of carcinogenesis in MSI and MSS sporadic colorectal carcinomas are suggested based on the observations of prevalence of mutations in APC, KRAS, TP53, and TGF-BII genes, i.e., genes commonly found involved in sporadic colorectal carcinomas. 60 This was evident in our study too, because MSI seemed to confer mutations in several of the genes reported to be involved in endometrial carcinoma. Although 10 of the 11 tumors exhibiting MSI had mutation in either of the genes, PTEN accounted for the majority, an observation in agreement with previous studies.…”

Section: Discussionsupporting

confidence: 59%

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul

Wïllén

Bendahl

et al. 2002

Cancer

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BACKGROUNDEndometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated.METHODSTo elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes.RESULTSMicrosatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/β‐catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I–II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, β‐catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or β‐catenin mutations, and all PTEN mutations occurred in diploid tumors.CONCLUSIONSThus, PTEN, KRAS, β‐catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability. Cancer 2002;94:2369–79. © 2002 American Cancer Society.DOI 10.1002/cncr.10498

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Section: Discussionsupporting

confidence: 59%

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul

Wïllén

Bendahl

et al. 2002

Cancer

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“…APC mutation is infrequent in MSI-H cancers (Konishi et al, 1996;Salahshor et al, 1999). However, b-catenin mutation is not found in sporadic CRC with high level of microsatellite instability (MSI-H) (Salahshor et al, 1999). These observations fit with the lack of abnormal b-catenin immunostaining in sporadic MSI-H cancers (Wong et al, 2002).…”

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

No major tumorigenic role for β-catenin in serrated as opposed to conventional colorectal adenomas

et al. 2003

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Intracellular redistribution of b-catenin through mutation of the adenomatous polyposis coli (APC) gene has been proposed as an early tumorigenic event in most colorectal tumours. In serrated adenoma (SA), a newly recognised subtype of colorectal adenoma, APC mutations are uncommon, and the contribution of b-catenin to tumorigenesis remains unclear. We compared intracellular localisation of b-catenin and presence of mutations in exon 3 of b-catenin between 45 SAs, with 71 conventional adenomas (CADs), and eight carcinomas invading the submucosa (SCAs). Widespread or focal nuclear b-catenin expression was demonstrated in 7% of SAs (three out of 45), 61% of CADs (43 out of 71), and 88% of SCAs (seven out of eight). Cytoplasmic immunostaining for b-catenin was demonstrated in 16% of SAs (seven out of 45), 77% of CADs (55 out of 71), and 88% of SCAs (seven out of eight). No mutation in exon 3 of b-catenin was found in SAs or SCAs, while 7% of CADs (five out of 71) had b-catenin mutations. No nuclear or cytoplasmic expression of b-catenin was observed in the hyperplastic or conventionally adenomatous epithelium of mixed-type SAs. These findings suggest that b-catenin mutation is unlikely to contribute to the tumorigenesis in SA, and that intracellular localisation of b-catenin may not be associated with an early event of the tumour progression in most SAs.

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“…45,46 (6) Although oncogenic mutation of b-catenin has been linked with MSI-H CRC, this association is only with Lynch syndrome (and only around 20% of these) and not in MLH1-negative CRC. 41,46 Therefore, pERK may not function in isolation as a prognostic factor in CRC (the same observation was made by by Wang et al 13 in breast cancer), but may be implicated in CRC progression through its interactions with the wnt signaling pathway and RHAMM.…”

Section: Discussionmentioning

confidence: 72%

“…This finding leads to the hypothesis that pERK is involved in the mechanism of tumor progression of MMR-proficient CRC and Lynch syndrome by interacting with the wnt signaling pathway and RHAMM: (1) KRAS mutation is found in approximately 35% of unselected CRCs, whereas it is mutated at a particularly low frequency in sporadic MSI-H cancers. [38][39][40][41][42] (2) The molecule ERK, a member of the MAPK pathway, is activated by a cascade of phophorylation events downstream from the ras proto-oncogene. 8 (3) Intracellular and cell surface RHAMM isoforms are important for the activation of ERK by PDGF (platelet-derived growth factor) and mutant (activated) RAS, respectively, while intracellular RHAMMv4 overexpression activates ERK.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

et al. 2006

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RHAMM, a member of the microtubule-associated protein family that interacts with the mitogen-activated protein kinase pathway, is associated with tumor progression, aggressive disease and shortened survival in several tumor types. This study aimed to determine the prognostic value of RHAMM in colorectal cancer (CRC). A series of 1420 unselected, nonconsecutive CRC resections were subdivided into three groups: (1) DNA mismatch repair (MMR)-proficient, (2) MLH1 negative and (3) presumed Lynch syndrome. Immunohistochemical analysis of RHAMM expression (0 vs 40%), increasing expression (increasing percentage positivity) and complete expression (100 vs o100%) was performed using tissue microarray technique and the results were correlated with clinicopathological parameters. Fifty-seven tissue samples of normal colonic mucosa were included as a control group. In a univariate analysis increasing and complete expression of RHAMM were associated with higher N stage (P ¼ 0.023 and 0.021) and worse survival (Po0.0001) in MMR-proficient CRC. Complete expression of RHAMM was associated with worse survival in presumed Lynch syndrome (P ¼ 0.016). In MLH1-negative CRC there was no association between RHAMM expression and the clinicopathological features. In a multivariate analysis, increasing RHAMM expression was an independent adverse prognostic factor in MMR-proficient CRC (Po0.0001) and complete expression in MMR-proficient CRC and presumed Lynch syndrome (Po0.0001 and P ¼ 0.031, respectively). Nuclear pERK expression was associated with increasing RHAMM expression in MMR-proficient CRC (P ¼ 0.012) and with complete RHAMM expression in presumed HNPCC (P ¼ 0.03). Increasing and complete RHAMM expressions are independent adverse prognostic factors in MMR-proficient CRC and presumed Lynch syndrome.

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Colorectal cancer with and without microsatellite instability involves different genes

Cited by 121 publications

References 32 publications

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

No major tumorigenic role for β-catenin in serrated as opposed to conventional colorectal adenomas

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

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