Microsatellite instability and DNA ploidy in colorectal cancer

Søreide, Kjetil; Slewa, Aida; Stokkeland, Pål Johan; Diermen, Bianca van; Janssen, Emiel A. M.; Søreide, Jon Arne; Baak, Jan P. A.; Kørner, Hartwig

doi:10.1002/cncr.24024

Cited by 39 publications

(28 citation statements)

References 38 publications

(75 reference statements)

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“…35 High-level microsatellite instability (MSI-H), as demonstrated in $ 15% of sporadic CRCs, also displays sex specificity in that MSI-H (sporadic) tumors occur predominantly in older females, and 90% of these sporadic MSI-H tumors occur in the proximal colon. 36,37 Differential expression of hormonal and other receptors across the length of the colon and rectum could conceivably modulate risk in a sex-and subsite-specific manner, which may change with age (female menopause), and some investigations have focused on expression of estrogen receptors a and b across the colon [38][39][40] ; however, the etiological role of these receptors is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age

Murphy¹,

Devesa²,

Cross³

et al. 2011

Intl Journal of Cancer

210

128

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Although incidence of colorectal cancer (CRC) in the United States has declined in recent years, rates remain higher in men than in women and the male‐to‐female incidence rate ratio (MF IRR) increases progressively across the colon from the cecum to the rectum. Rates among races/ethnicities other than Whites or Blacks have not been frequently reported. To examine CRC rates by sex across anatomic subsite, age and racial/ethnic groups, we used the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program for cases diagnosed among residents of 13 registries during 1992–2006. Incidence rates were expressed per 100,000 person‐years and age‐adjusted to the 2000 US Standard Population; MF IRR and 95% confidence intervals were also calculated. Among each racial/ethnic group, the MF IRR increased fairly monotonically from close to unity for cecal cancers to 1.81 (Hispanics) for rectal cancers. MF IRRs increased with age most rapidly for distal colon cancers from <1.0 at ages <50 years to 1.4–1.9 at older ages. The MF IRR for rectal cancers also rose with age from about 1.0 to 2.0. For proximal cancer, the MF IRR was consistently <1.5; among American Indian/Alaska Natives, it was <1.0 across all ages. The MF IRRs for CRC vary markedly according to subsite and age but less by racial/ethnic group. These findings may partially reflect differences in screening experiences and access to medical care but also suggest that etiologic factors may be playing a role.

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Section: Discussionmentioning

confidence: 99%

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age

Murphy¹,

Devesa²,

Cross³

et al. 2011

Intl Journal of Cancer

210

128

View full text Add to dashboard Cite

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“…Microsatellite instability has been linked to proximal location [37] and has been consistently linked to BRAF mutation in colorectal cancer [3,4,6]: one review described BRAF mutation as a 'hallmark' of MSI tumours [38]. Poor differentiation has also been linked to BRAF mutation in previous studies [39,40] as well as microsatellite instability [41]. Taken together, these data confirm that the clinicopathological signature of BRAF mutated colorectal cancer includes proximal location, microsatellite instability and poor differentiation.…”

Section: Discussionmentioning

confidence: 99%

Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study

et al. 2010

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Background: BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer. This study investigates the associations between BRAF and K-ras mutations and clinicopathological, lifestyle and dietary factors in colorectal cancers. Methods: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries. Results: BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p < 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02). Conclusion: These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.

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“…Investigators have proposed distinct classification of 3, 4 and 5 groups in the past [14,24–26], but none has yet reached clinical practice. The extent of overlap between these phenotypic groups has been investigated [5,14,16,25,45–47], but the clinical implications of the molecular phenotypes are so far vague. The use of different methodology, definitions, scoring criteria, and differences in the type of patient material investigated make comparisons difficult, which is underscored by the overlap found in this study.…”

Section: Discussionmentioning

confidence: 99%

“…MSI and BRAF mutation status is mainly observed in the same samples, and both are suggested to be clinically relevant [14,15]. Patients with tumors of the MSI type are associated with specific clinical, molecular and histopathological features [4,16–19], and have a better prognosis compared to patients with CNV tumors [20]. Furthermore, the particular tumor location along the colorectal continuum is associated with site-specific differences in the genetic composition of tumors.…”

Section: Introductionmentioning

confidence: 99%

Molecular Subtypes in Stage II-III Colon Cancer Defined by Genomic Instability: Early Recurrence-Risk Associated with a High Copy-Number Variation and Loss of RUNX3 and CDKN2A

et al. 2015

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ObjectiveWe sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer.MethodsWe sought to investigate various molecular subtypes defined by instability at microsatellites (MSI), changes in methylation patterns (CpG island methylator phenotype, CIMP) or copy number variation (CNV) in 8 genes. Stage II-III colon cancers (n = 64) were investigated by methylation-specific multiplex ligated probe amplification (MS-MLPA). Correlation of CNV, CIMP and MSI, with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni- and multivariate regression.ResultsThe CIMP phenotype occurred in 34% (22/64) and MSI in 27% (16/60) of the tumors, with noted CIMP/MSI overlap. Among the molecular subtypes, a high CNV phenotype had an associated odds ratio (OR) for recurrence of 3.2 (95% CI 1.1-9.3; P = 0.026). Losses of CACNA1G (OR of 2.9, 95% CI 1.4-6.0; P = 0.001), IGF2 (OR of 4.3, 95% CI 1.1-15.8; P = 0.007), CDKN2A (p16) (OR of 2.0, 95% CI 1.1-3.6; P = 0.024), and RUNX3 (OR of 3.4, 95% CI 1.3-8.7; P = 0.002) were associated with early recurrence, while MSI, CIMP, KRAS or BRAF V600E mutations were not. The CNV was significantly higher in deceased patients (CNV in 6 of 8) compared to survivors (CNV in 3 of 8). Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk-model for early recurrence.ConclusionsA high copy number variation phenotype is a strong predictor of early recurrence and death, and may indicate a dose-dependent relationship between genetic instability and outcome. Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation.

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Microsatellite instability and DNA ploidy in colorectal cancer

Cited by 39 publications

References 38 publications

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age

Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study

Molecular Subtypes in Stage II-III Colon Cancer Defined by Genomic Instability: Early Recurrence-Risk Associated with a High Copy-Number Variation and Loss of RUNX3 and CDKN2A

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