The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients

Bohaumilitzky, Lena; Kluck, Klaus; Hüneburg, Robert; Gallon, Richard; Nattermann, Jacob; Kirchner, Martina; Kristiansen, Glen; Hommerding, Oliver; Pfuderer, Pauline L.; Wagner, Lelia; Echterdiek, Fabian; Kösegi, Svenja; Müller, Nico; Fischer, Konstantin; Nelius, Nina; Hartog, Ben; Borthwick, Gillian M.; Busch, Elena; Haag, Georg Martin; Bläker, Hendrik; Möslein, Gabriela; Doeberitz, Magnus von Knebel; Seppälä, Toni T.; Ahtiainen, Maarit; Mecklin, Jukka‐Pekka; Bishop, D. Timothy; Burn, John; Budczies, Jan; Kloor, Matthias; Ahadova, Aysel

doi:10.1053/j.gastro.2021.11.029

Cited by 33 publications

(35 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6 Furthermore, among the MMR genes, there is variable penetrance with higher prevalence of PMS2 and MSH6 variants in the general population but lower frequencies of CRC compared to MLH1 and MSH2. [7][8][9] Interestingly, all three of our patients were male and were carriers of a mutation in the MLH1 and MSH2 genes, which would suggest increased risk for development of CRC based on results of this meta-analysis.…”

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

Polygenic early‐onset colorectal cancer in pediatric patients

Phen

Berens

Moriarty

et al. 2022

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Colorectal cancer in the pediatric population is a rare but transpirable phenomenon.The occurrence should prompt suspicion for underlying genetic mutations in the setting of a hereditary cancer predisposition syndrome. In this series, we outline three pediatric patients with colonic adenocarcinoma who were found to have one or more germline mutations. The presence of compound mutations may lead to a hypermutator phenotype resulting in earlier presentation of colorectal cancer in childhood and adolescence. The diagnosis of colorectal cancer in pediatric patients warrants timely recognition, multigene panel testing, genetic counseling for the patient and family, and

show abstract

Section: Discussionmentioning

confidence: 70%

“…LS has a 30%-80% lifetime risk for CRC, and risk modifiers remain largely unknown. [6][7][8] Given the rarity of CRC in the pediatric population, limited information is available about the clinical and genetic features and patient outcomes. Herein, we present a series of three pediatric patients with polygenic early-onset CRC.…”

Section: Introductionmentioning

confidence: 99%

Polygenic early‐onset colorectal cancer in pediatric patients

Phen

Berens

Moriarty

et al. 2022

Pediatric Blood & Cancer

View full text Add to dashboard Cite

show abstract

“…Several DE c-miRs have been implicated to sporadic cancer progression (41,42). To study this in our dataset, we compared sporadic rectal cancer patients to non-LS controls.…”

Section: Resultsmentioning

confidence: 99%

Systemic circulating microRNA landscape in Lynch syndrome

Sievänen

Korhonen

Jokela

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

MicroRNAs (miRs) are non-coding RNA-molecules that regulate gene expression. Global circulating miR (c-miR) expression patterns (c-miRnome) change with carcinogenesis in various sporadic cancers. Therefore, aberrantly expressed c-miRs could have diagnostic, predictive and prognostic potential in molecular profiling of cancers. c-miR functions in carriers of inherited pathogenic mismatch-repair gene variants (path_MMR), also known as Lynch syndrome (LS), have remained understudied. LS cohort provides an ideal population for biomarker mining due to increased lifelong cancer risk and excessive cancer occurrence. Using high-throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c-miRnomes of path_MMR carriers. Our discovery cohort included 81 healthy path_MMR carriers and 37 non-LS controls. Our analysis also included cancer cohort comprised of 13 path_MMR carriers with varying cancers and 24 sporadic rectal cancer patients. We showed for the first time that c-miRnome can discern healthy path_MMR carriers from non-LS controls but does not distinguish healthy path_MMR carriers from cancer patients with or without path_MMR. Our c-miR expression analysis combined with in silico tools suggest ongoing alterations of biological pathways shared in LS and sporadic carcinogenesis. We observed that these alterations can produce a c-miR signature which can be used to track oncogenic stress in cancer-free path_MMR carriers. Thus, c-miRs hold potential in monitoring which cancer patients would require more intensive surveillance or clinical management.

show abstract

“…88 Moreover, pronounced local immune responses in Lynch syndrome have been demonstrated in Lynch colorectal cancers, adenomas, MMRd crypts and even entirely normal-appearing colonic mucosa. [89][90][91][92] All these observations together suggest that active surveillance by the adaptive immune system plays a major role in controlling and suppressing the outgrowth of MMRd cancers in individuals affected by Lynch syndrome. Immune surveillance thus likely contributes to the limited penetrance of the disease 60 63 through the elimination of precancerous MMRd cells.…”

Section: Evidence For Endogenous Immune Surveillance In Lynch Syndromementioning

confidence: 96%

Vaccines for immunoprevention of DNA mismatch repair deficient cancers

Hernandez‐Sanchez

Grossman

Yeung

et al. 2022

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

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.

show abstract

The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients

Cited by 33 publications

References 68 publications

Polygenic early‐onset colorectal cancer in pediatric patients

Polygenic early‐onset colorectal cancer in pediatric patients

Systemic circulating microRNA landscape in Lynch syndrome

Vaccines for immunoprevention of DNA mismatch repair deficient cancers

Contact Info

Product

Resources

About