Dataset Information

Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma.

ABSTRACT:

Purpose

The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.

Experimental design

A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.

Results

Twenty-six percent (26/100; 95% confidence interval, 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).

Conclusions

When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

SUBMITTER: Latham A

PROVIDER: S-EPMC7925361 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer cells. However, weak immunogenicity and the mutational heterogeneity in many cancers have dampened cancer vaccine successes. With increasing information about mutational landscapes of cancers, mutational neoantigens can be predicted computationally to elicit strong immune responses by CD8 +cytotoxic T cells as major mediators of anticancer immune response. Neoantigens are potentially more robust immunogens and have revived interest in cancer vaccines. Cancers with deficiency in DNA mismatch repair have an exceptionally high mutational burden, including predictable neoantigens. Lynch syndrome is the most common inherited cancer syndrome and is caused by DNA mismatch repair gene mutations. Insertion and deletion mutations in coding microsatellites that occur during DNA replication include tumorigenesis drivers. The induced shift of protein reading frame generates neoantigens that are foreign to the immune system. Mismatch repair-deficient cancers and Lynch syndrome represent a paradigm population for the development of a preventive cancer vaccine, as the mutations induced by mismatch repair deficiency are predictable, resulting in a defined set of frameshift peptide neoantigens. Furthermore, Lynch syndrome mutation carriers constitute an identifiable high-risk population. We discuss the pathogenesis of DNA mismatch repair deficient cancers, in both Lynch syndrome and sporadic microsatellite-unstable cancers. We review evidence for pre-existing immune surveillance, the three mechanisms of immune evasion that occur in cancers and assess the implications of a preventive frameshift peptide neoantigen-based vaccine. We consider both preclinical and clinical experience to date. We discuss the feasibility of a cancer preventive vaccine for Lynch syndrome carriers and review current antigen selection and delivery strategies. Finally, we propose RNA vaccines as having robust potential for immunoprevention of Lynch syndrome cancers.

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