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.
