Relationship of Emast and Microsatellite Instability Among Patients with Rectal Cancer
Bikash Devaraj*1,2, Sonia Ramamoorthy1, Robert S. Sandler5, Temitope O. Keku5, Aaron Lee2, Linda Luo1, Kathie Mcguire4, Betty L. Cabrera7, Katsumi Miyai3, John M. Carethers6,2
1Surgery, UC San Diego, San Diego, CA; 2Gastroenterology, UC San Diego, San Diego, CA; 3Pathology, UC San Diego, San Diego, CA; 4Biology, San Diego State University, San Diego, CA; 5Internal Medicine, North Carolina - Chapel Hill, Chapel Hill, NC; 6Internal Medicine, University of Michigan, Ann Arbor, MI; 7Pediatrics, UC San Diego, San Diego, CA
Background. Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in two-thirds of sporadic colon cancers (and other cancers) and is associated with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI) in which hypermethlation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and relaxation of MMR function with the subsequent biological consequences not known. We evaluated EMAST and MSI in a population-based cohort of rectal cancers, as this has not been previously determined.Methods. We analyzed 147 sporadic cases of rectal cancer using 5 tetranucleotide microsatellite markers and NCI-recommended MSI (mono and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the PCR products, and determined positive if at least 2 loci were found to have frameshifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage, and examined a subset of 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 (3 males, 2 African American) and 49/147 (33%) demonstrated EMAST (frequency of markers positive are in Table 1). Rectal tumors from African Americans were more likely to show EMAST than Caucasians (17/36, 47% vs 30/105, 29%, P=0.04), and approached an association with advanced stage (18/29, 62% vs local disease 11/29, 38%, P=0.06). There was no association between EMAST and gender (female 19/53, 36% vs male 28/88, 32% P>0.05). In the subset of tumors analyzed for lymphocytes histologically, EMAST was more prevalent in rectal tumors that showed peri- or intra-tumoral infiltration compared to those without.Conclusions. The frequency of EMAST in rectal cancers (~33%) is less than reported for colon cancer (~66%), 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 is under investigation, but its association with immune cell infiltration suggests inflammation may play a role for its development.
Frequency of EMAST Marker Mutations
| Loci | MYCL1 | 20S85 | 8S321 | 20S82 | 9S242 |
| # times mutated (N=147) | 35 | 9 | 43 | 43 | 35 |
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