Microsatellite instability and survival in rectal cancer

Samowitz, Wade S.; Curtin, Karen; Wolff, Roger K.; Tripp, Sheryl R.; Caan, Bette J.; Slattery, Martha L.

doi:10.1007/s10552-009-9410-3

Cited by 81 publications

(83 citation statements)

References 23 publications

(27 reference statements)

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“…Unlike MSI colon cancers, where there is a predominance of proximal cancers in elderly females, one Japanese group found that over a third of MSI CRC in men developed in the rectum (Ishikubo et al, 2004). dMMR rectal cancer appears to have other unique features, with a majority mucinous component (Takemoto et al, 2004), and a reduced incidence of MLH1 promoter hypermethylation and expression of BRAF mutations compared to dMMR colon cancer (Samowitz et al, 2009) The later may be explained by the lower frequency of hMLH1 promoter methylation in Lynch syndrome than in sporadic dMMR colorectal cancers (Herman et al, 1998;Kuismanen et al, 2000). With a reduced incidence of BRAF mutations one would expect dMMR rectal cancer to have an improved prognosis, however, initial prognostic studies were conflicting.…”

Section: Rectal Cancer With Msimentioning

confidence: 99%

“…With a reduced incidence of BRAF mutations one would expect dMMR rectal cancer to have an improved prognosis, however, initial prognostic studies were conflicting. One reported 5-year overall survival (OS) of 50% for 22 dMMR rectal cancers (Samowitz et al, 2009), and another reported 3-year disease free survival (DFS) of 90% for 20 dMMR rectal cancers (Hong et al, 2012), Nevertheless, in the largest, most recent clinical series dMMR rectal cancer was confirmed to have an outstanding prognosis compared with pMMR disease, with a 5-year OS and DFS of 90.6% (de Rosa et al, 2016) and 70% (Park et al, 2012) respectively for locally advanced rectal cancer and 5-year OS of 50% for metastatic CRC (Brouquet et al, 2010).…”

Section: Rectal Cancer With Msimentioning

confidence: 99%

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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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Section: Rectal Cancer With Msimentioning

confidence: 99%

Section: Rectal Cancer With Msimentioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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“…Along with others, we have reported a worse prognosis in colorectal cancer patients with CIMP-low or CIMP-high, compared with CIMPnegative tumors, particularly in combination with MSS. 4,[9][10][11][12] However, results from other large studies have not been entirely consistent, [13][14][15][16][17][18] and consensus has thus not been reached. One factor contributing to the discrepancy of results in the many studies is the lack of information regarding BRAF mutation, which has shown to be a major confounding factor in studies of CIMP status and colorectal cancer patient survival.…”

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confidence: 97%

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

et al. 2011

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The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eightgene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score Z7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score r4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P ¼ 0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

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“…The project was a population-based cohort assessing rectal cancer and epidemiological data from 33 counties in North Carolina. 17 Paraffin-embedded normal and tumor tissues were cut into 5-μm sections, and microdissection was performed under microscopy. Genomic DNA was isolated using GeneReleaser (Bioventure, Inc.) and then treated with proteinase K. 18 …”

Section: Patient Tissue and Dna Extractionmentioning

confidence: 99%

“…17 We utilized five tetranucleotide markers that have been traditionally used to define EMAST, and we considered rectal tumors as EMAST if at least two markers demonstrated instability. Based on this definition, 49/147 (33%) demonstrated EMAST.…”

Section: Emast Is Common and Msi Is Rare In Rectal Cancersmentioning

confidence: 99%

973 Relationship of EMAST and Microsatellite Instability Among Patients With Rectal Cancer

Devaraj¹,

Ramamoorthy²,

Sandler³

et al. 2010

Gastroenterology

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Background Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a populationbased cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. Methods We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and NationalCancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Results Among this cohort of patients with rectal cancer (mean age 62.2±10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p=0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p=0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p=0.0001). Conclusions EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development.

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Microsatellite instability and survival in rectal cancer

Cited by 81 publications

References 23 publications

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

973 Relationship of EMAST and Microsatellite Instability Among Patients With Rectal Cancer

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