Is HLA type a possible cancer risk modifier in Lynch syndrome?. Issue 10 (14th October 2022)

• Record Type: Journal Article
• Authors: Ahadova, Aysel; Witt, Johannes; Haupt, Saskia; Gallon, Richard; Hüneburg, Robert; Nattermann, Jacob; ten Broeke, Sanne; Bohaumilitzky, Lena; Hernandez‐Sanchez, Alejandro; Santibanez‐Koref, Mauro; Jackson, Michael S.; Ahtiainen, Maarit; Pylvänäinen, Kirsi; Andini, Katarina; Grolmusz, Vince Kornel; Möslein, Gabriela; Dominguez‐Valentin, Mev; Møller, Pål; Fürst, Daniel; Sijmons, Rolf; Borthwick, Gillian M.; Burn, John; Mecklin, Jukka‐Pekka; Heuveline, Vincent; von Knebel Doeberitz, Magnus; Seppälä, Toni; Kloor, Matthias
• Is Part Of: International journal of cancer. Volume 152:Issue 10(2023)
• Page Start: 2024
• Page End: 2031
• Publication Date: 2022-10-14
• Subjects: cancer immunoediting -- HLA genotype -- immune surveillance -- Lynch syndrome -- personalized cancer risk; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34312
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR‐deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR‐deficient cancers leads to a counter‐selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/ ), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors. Abstract :