Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Human Leukocyte Antigen-Allelic Variations May Influence the Age at Cancer Diagnosis in Lynch Syndrome

Lutricia Ndou
ORCID logo ,
Ramadhani Chambuso
ORCID logo ,
Ziyaad Valley-Omar
ORCID logo ,
George Rebello
,
Paul Goldberg
,
Adam Boutall
,
Ursula Algar
,
Raj Ramesar
*
Version 1 : Received: 6 March 2024 / Approved: 7 March 2024 / Online: 7 March 2024 (07:36:11 CET)

How to cite: Ndou, L.; Chambuso, R.; Valley-Omar, Z.; Rebello, G.; Goldberg, P.; Boutall, A.; Algar, U.; Ramesar, R. Human Leukocyte Antigen-Allelic Variations May Influence the Age at Cancer Diagnosis in Lynch Syndrome. Preprints 2024, 2024030412. https://doi.org/10.20944/preprints202403.0412.v1 Ndou, L.; Chambuso, R.; Valley-Omar, Z.; Rebello, G.; Goldberg, P.; Boutall, A.; Algar, U.; Ramesar, R. Human Leukocyte Antigen-Allelic Variations May Influence the Age at Cancer Diagnosis in Lynch Syndrome. Preprints 2024, 2024030412. https://doi.org/10.20944/preprints202403.0412.v1

Abstract

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

Keywords

Lynch syndrome; colorectal cancer; germline pathogenic variant MLH1:c.1528C>T; Human leukocyte antigen (HLA); age at cancer diagnosis; genetic risk modifiers; personalized cancer screening

Subject

Medicine and Pharmacology, Epidemiology and Infectious Diseases

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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