High-level Microsatellite Instability in Appendiceal Carcinomas

Abstract

High-level microsatellite instability (MSI-high) is found in approximately 15% of all colorectal adenocarcinomas (CRCs) and in at least 20% of right-sided cancers. It is most commonly due to somatic hypermethylation of the MLH1 gene promoter region, with familial cases (Lynch syndrome) representing only 2–3% of CRCs overall. In contrast to CRC, MSI-high in appendiceal adenocarcinomas is rare. Only four MSI-high appendiceal carcinomas and one MSI-high appendiceal serrated adenoma have been previously reported, and the prevalence of MSI in the appendix is unknown. We identified 108 appendiceal carcinomas from M. D. Anderson Cancer Center in which MSI status had been assessed by immunohistochemistry for the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 (n=83), polymerase chain reaction (n=7), or both (n=18). Three cases (2.8%) were MSI-high and one was MSI-low. The three MSI-high cases included: 1) a poorly differentiated nonmucinous adenocarcinoma with loss of MLH1/PMS2 expression, lack of MLH1 promoter methylation, and lack of BRAF gene mutation, but no detected germline mutation in MLH1 from a 39-year-old man; 2) an undifferentiated carcinoma with loss of MSH2/MSH6, but no detected germline mutation in MSH2 or TACSTD1, from a 59-year-old woman; and 3) a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with loss of MSH2/MSH6 expression, in a 38-year-old man with a strong family history of CRC who declined germline testing. When the overall group of appendiceal carcinomas was classified according to histologic features and precursor lesions, the frequencies of MSI-high were: 3 of 108 (2.8%) invasive carcinomas, 3 of 96 (3.1%) invasive carcinomas that did not arise from a background of goblet cell carcinoid, and 0 of 12 (0%) signet ring and mucinous carcinomas arising in goblet cell carcinoid tumors. These findings, in conjunction with the previously reported MSI-high appendiceal carcinomas, highlight the low prevalence of MSI in the appendix as compared to the right colon and suggest that MLH1 promoter methylation is not a mechanism for microsatellite instability in this location.

A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix

“…In contrast, MSI-high in appendiceal adenocarcinoma is reported to be rare with the prevalence of MSI being approximately 3% [8]. Of our series of 16 AMTs, there was no case with MLH1 and MSH2 protein loss, consistent with the previous report [8].…”

“…High-level microsatellite instability (MSI-high) is found in approximately 15% of all colorectal adenocarcinomas and in at least 20% of right-sided bowel cancers [8]. In contrast, MSI-high in appendiceal adenocarcinoma is reported to be rare with the prevalence of MSI being approximately 3% [8].…”

“…Overexpression of p53 is reported to be rare in appendiceal tumors [4,6], although KRAS mutation and p53 overexpression can be seen in half of pseudomyxoma peritonei (PMP) cases of appendiceal origin [7]. Furthermore, microsatellite instability is rare in appendiceal carcinoma, and hypermethylation is not a mechanism for genetic instability in these tumors [8] although some hyperplastic polyps and sessile serrated adenomas of the appendix show decreased expression of MLH1 and BRAF mutation is more common in serrated polyps [9]. The Wnt signaling pathway that involves ␤-catenin plays a critical role in colorectal carcinogenesis, and approximately 90% of cases of colorectal carcinoma express nuclear ␤-catenin.…”

Chromatin Memory in the Development of Human Cancers

“…Promoter hypermethylation induced inactivation of BRCA1 and MLH1 results in increased p53 gene mutation in human sporadic breast cancer [61,62] and microsatellite instability (MSI) in sporadic colorectal cancer [63] respectively. MSI in sporadic colorectal cancer are overwhelmingly due to epigenetic silencing of the MHL1 gene by hypermethylation of its promoter; this hypermethylation usually occurs in a background of widespread CpG island promoter methylation, also referred to as the CpG island methylator phenotype; which has also been found in gastric, lung, liver, ovarian, glioblastomas, endometrial and breast cancers [64].…”

Genomics of peritoneal surface malignancies

“…20 High-level microsatellite instability (MSI) is also rare (3%) in appendiceal cancers, whereas approximately 15% of colorectal carcinomas (CRCs) display highlevel MSI. 27,28 Sio et al identified MCL1 and JUN1 amplification in 30% of PMP cases using next-generation sequencing assay with Illumina HiSeq2000 platform. 24 MCL1 is a BCL2 family anti-apoptotic gene, and its overexpression may contribute to chemotherapy resistance to 5-fluorouracil, which is given commonly for PMP dur- Original Article from PSOGI Congress High variation in mutation rates is likely from a small number of patients, the difference in cell enrichment methods and genome sequencing techniques in individual studies.…”