A1 Journal article (refereed)
Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort (2024)

Sipilä, Lauri J., Aavikko, Mervi, Ravantti, Janne, Martin, Samantha, Kuopio, Teijo, Lahtinen, Laura, FinnGen, Peltomäki, Päivi, Mecklin, Jukka-Pekka, Aaltonen, Lauri A., Seppälä, Toni T. (2024). Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort. Familial Cancer, Early online. https://doi.org/10.1007/s10689-024-00400-4

JYU authors or editors

Publication details

All authors or editors: Sipilä, Lauri J.; Aavikko, Mervi; Ravantti, Janne; Martin, Samantha; Kuopio, Teijo; Lahtinen, Laura; FinnGen; Peltomäki, Päivi; Mecklin, Jukka-Pekka; Aaltonen, Lauri A.; et al.

Journal or series: Familial Cancer

ISSN: 1389-9600

eISSN: 1573-7292

Publication year: 2024

Publication date: 07/06/2024

Volume: Early online

Publisher: Springer

Publication country: Netherlands

Publication language: English

DOI: https://doi.org/10.1007/s10689-024-00400-4

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/95774

Abstract

Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in MLH1, in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a large genotyped cohort comprising approximately 10% of the current Finnish population, and validated the MLH1 founder variant status of identified individuals residing in the Central Finland Biobank catchment area. A consensus sequence flanking the deletion was identified in whole genome sequences of six LS individuals with the founder variant. Genotype data of 212,196 individuals was queried for regional matches to the consensus sequence. Enrichment of cancer and age at cancer onset was compared between matching and non-matching individuals. Variant status was validated for a subset of the identified individuals using a polymerase chain reaction assay. Allelic matches in a chosen target region was detected in 348 individuals, with 89 having a cancer diagnosis (Bonferroni-adjusted p-value = 1), 20 a familial cancer history (p-adj. < .001), with mean age of onset of cancer being 53.6 years (p-adj. = .002). Eighteen of potential variant carriers had been sampled by the Central Finland Biobank, of which four (22%) were validated as true variant carriers. The workflow we have employed identifies MLH1 exon 16 deletion variant carriers from population-wide SNP genotyping data. An alternative design will be sought to limit false positive findings. Large genotyped cohorts provide a potential resource for identification and prevention of hereditary cancer.

Keywords: cancerous diseases; cancer of the large intestine; Lynch syndrome; hereditary diseases; hereditary predisposition; genotype; oncogenes; diagnosis; biobanks; cohort study

Free keywords: lynch syndrome; mismatch repair deficiency; biobank; genotype association; personalized medicine

Contributing organizations

Ministry reporting: Yes

VIRTA submission year: 2024

Preliminary JUFO rating: 1