Is <scp>HLA</scp> type a possible cancer risk modifier in Lynch syndrome?

Ahadova, Aysel; Witt, Johannes; Haupt, Saskia; Gallon, Richard; Hüneburg, Robert; Nattermann, Jacob; Broeke, Sanne W. ten; Bohaumilitzky, Lena; Hernandez‐Sanchez, Alejandro; Santibanez‐Koref, Mauro; Jackson, Michael S.; Ahtiainen, Maarit; Pylvänäinen, Kirsi; Andini, Katarina; Grolmusz, Vince; Möslein, Gabriela; Dominguez‐Valentin, Mev; Møller, Pål; Fürst, Daniel E.; Sijmons, Rolf H.; Borthwick, Gillian M.; Burn, John; Mecklin, Jukka‐Pekka; Heuveline, Vincent; Doeberitz, Magnus von Knebel; Seppälä, Toni T.; Kloor, Matthias

doi:10.1002/ijc.34312

Cited by 7 publications

(15 citation statements)

References 68 publications

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“…differences in cancer risks and age of onset. No data on this is currently available, but a new initiative has been established to further investigate this (INDICATE, http://indicate-lynch.org/) (94). Analysing such data in a MMR gene-stratified manner seems critical given the differences in preferential carcinogenic pathways.…”

Section: Influence Of Hla Genotypementioning

confidence: 99%

PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.

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Section: Influence Of Hla Genotypementioning

confidence: 99%

PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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“…Thus, although the shared nature of the driver cMS mutations among different patients and tumors allows the use of a limited set of recurrent candidate neoantigens, response to vaccination and tumor-preventive effectiveness might be substantially improved by the adaptation of the epitopes derived from these neoantigens to the specific HLA type of an individual. Accounting for HLA type specificity is therefore an important task for future immune prevention and interception approaches, potentially enabling higher vaccine effectiveness by individualization of the vaccine formulation to a person’s HLA genotype ( 100 ).…”

Section: Hla Genotype and Tumor Antigen Evolutionmentioning

confidence: 99%

“…If HLA type in fact influences immune surveillance, the HLA genotype may influence the tumor incidence or tumor risk in LS carriers. Studies analyzing the possible effect of the individual HLA type on cancer risk in LS have been initiated ( 100 , 103 ). The findings expected from these studies will guide the future development of next-generation HLA-adapted individualized neoantigen vaccines.…”

Section: Hla Genotype and Tumor Antigen Evolutionmentioning

confidence: 99%

Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies

et al. 2023

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Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers. While significant progress has been made in the timely identification of germline pathogenic variant carriers and monitoring and early detection of precancerous lesions, cancer-risk reduction strategies are still centered around endoscopic or surgical removal of neoplastic lesions and susceptible organs. Safe and effective cancer prevention strategies are critically needed to improve the life quality and longevity of LS and other HCS carriers. The era of precision oncology driven by recent technological advances in tumor molecular profiling and a better understanding of genetic risk factors has transformed cancer prevention approaches for at-risk individuals, including LS carriers. MMR deficiency leads to the accumulation of insertion and deletion mutations in microsatellites (MS), which are particularly prone to DNA polymerase slippage during DNA replication. Mutations in coding MS give rise to frameshift peptides (FSP) that are recognized by the immune system as neoantigens. Due to clonal evolution, LS tumors share a set of recurrent and predictable FSP neoantigens in the same and in different LS patients. Cancer vaccines composed of commonly recurring FSP neoantigens selected through prediction algorithms have been clinically evaluated in LS carriers and proven safe and immunogenic. Preclinically analogous FSP vaccines have been shown to elicit FSP-directed immune responses and exert tumor-preventive efficacy in murine models of LS. While the immunopreventive efficacy of “off-the-shelf” vaccines consisting of commonly recurring FSP antigens is currently investigated in LS clinical trials, the feasibility and utility of personalized FSP vaccines with individual HLA-restricted epitopes are being explored for more precise targeting. Here, we discuss recent advances in precision cancer immunoprevention approaches, emerging enabling technologies, research gaps, and implementation barriers toward clinical translation of risk-tailored prevention strategies for LS carriers. We will also discuss the feasibility and practicality of next-generation cancer vaccines that are based on personalized immunogenic epitopes for precision cancer immunoprevention.

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“…On the other hand, other associations between HLA genotypes and the onset of other cancers have been demonstrated, in fact , It has been shown that in Lynch syndrome carrier’s, HLA genotype plays an important role in the presentation of frameshift peptides (FSP) antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

HLA-B58 and HLA-B27 Play a Role in the Development of Acute Leukemia: A Case Control Study

Habour Nouar,

Yafour,

Youcef

et al. 2024

Asian Pac J Cancer Prev

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Background: Acute leukemia (AL) constitutes a group of malignant hematological diseases with multifactor origins. Some human leukocyte alleles (HLA) may be important genetic risk factors for development of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It is still unknown whether there is a relationship between ALL and AML with some alleles of the major histocompatibility complex. Our study looks specifically at western and southwest Algerian populations. Method: Using the polymerase chain reaction with the sequence specific probe (PCR- SSP) method, we investigated the relationship of HLA-B alleles in 163 Algerian AL patients and 293 controls from the same ethnic origin. The study ran from 2013 – 2020. Results: Allele frequencies of HLA-B*27 and HLA-B*58 was higher in AL patients compared with control individuals; p=0.05 and p=0.03 respectively. Interestingly, all patients carrying HLA-B*27 allele and 88% of patients carrying HLA-B*58 allele had AML. However, there were no significant differences when we compared these results with the rest of AL group (HLA-B*X allele) (p=0.387). Response to induction chemotherapy treatment were comparable between the two patient groups 67% and 65% (p=0.978) respectively. Conclusion: These results suggest that the HLA-B*27 and HLA-B*58, may be factors predisposing individuals to acute leukemia, in west and southwest Algerian patients. A large-scale study is still needed to confirm these findings.

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Is HLA type a possible cancer risk modifier in Lynch syndrome?

Cited by 7 publications

References 68 publications

PMS2-associated Lynch syndrome: Past, present and future

PMS2-associated Lynch syndrome: Past, present and future

Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies

HLA-B58 and HLA-B27 Play a Role in the Development of Acute Leukemia: A Case Control Study

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Is HLA type a possible cancer risk modifier in Lynch syndrome?

Cited by 7 publications

References 68 publications

PMS2-associated Lynch syndrome: Past, present and future

PMS2-associated Lynch syndrome: Past, present and future

Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies

HLA-B*58 and HLA-B*27 Play a Role in the Development of Acute Leukemia: A Case Control Study

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HLA-B58 and HLA-B27 Play a Role in the Development of Acute Leukemia: A Case Control Study