A1 Journal article (refereed)
Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors (2024)


Olkinuora, A., Mäki-Nevala, S., Ukwattage, S., Ristimäki, A., Ahtiainen, M., Mecklin, J.-P., & Peltomäki, P. (2024). Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors. Frontiers in Oncology, 14, Article 1378392. https://doi.org/10.3389/fonc.2024.1378392


JYU authors or editors


Publication details

All authors or editors: Olkinuora, Alisa; Mäki-Nevala, Satu; Ukwattage, Sanjeevi; Ristimäki, Ari; Ahtiainen, Maarit; Mecklin, Jukka-Pekka; Peltomäki, Päivi

Journal or series: Frontiers in Oncology

eISSN: 2234-943X

Publication year: 2024

Publication date: 25/04/2024

Volume: 14

Article number: 1378392

Publisher: Frontiers Media SA

Publication country: Switzerland

Publication language: English

DOI: https://doi.org/10.3389/fonc.2024.1378392

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/94586


Abstract

Background: Lynch syndrome (LS) is an autosomal dominant multi-organ cancer syndrome with a high lifetime risk of cancer. The number of cumulative colorectal adenomas in LS does not generally exceed ten, and removal of adenomas via routine screening minimizes the cancer burden. However, abnormal phenotypes may mislead initial diagnosis and subsequently cause suboptimal treatment.
Aim: Currently, there is no standard guide for the care of multiple colorectal adenomas in LS individuals. We aimed to shed insight into the molecular features and reasons for multiplicity of adenomas in LS patients.
Methods: We applied whole exome sequencing on nine adenomas (ten samples) and three assumed primary carcinomas (five samples) of an LS patient developing the tumors during a 21-year follow-up period. We compared the findings to the tumor profiles of two additional LS cases ascertained through colorectal tumor multiplicity, as well as to ten adenomas and 15 carcinomas from 23 unrelated LS patients with no elevated adenoma burden from the same population. As LS associated cancers can arise via several molecular pathways, we also profiled the tumors for CpG Island Methylator Phenotype (CIMP), and LINE-1 methylation.
Results: All tumors were microsatellite unstable (MSI), and MSI was present in several samples derived from normal mucosa as well. Interestingly, frequent frameshift variants in RNF43 were shared among substantial number of the tumors of our primary case and the tumors of LS cases with multiple tumors but almost absent in our control LS cases. The RNF43 variants were completely absent in the normal tissue, indicating tumor-associated mutational hotspots. The RNF43 status correlated with the mutational signature SBS96. Contrary to LS tumors from the reference set with no elevated colorectal tumor burden, the somatic variants occurred significantly more frequently at C>T in the CpG context, irrespective of CIMP or LINE-1 status, potentially indicating other, yet unknown methylation-related mechanisms. There were no signs of somatic mosaicism affecting the MMR genes. Somatic variants in APC and CTNNB1 were unique to each tumor.
Conclusion: Frequent somatic RNF43 hot spot variants combined with SBS96 signature and increased tendency to DNA methylation may contribute to tumor multiplicity in LS.


Keywords: Lynch syndrome; exome sequencing; tumours; bowel cancer

Free keywords: Lynch syndrome; exome sequencing; panel sequencing; multiple adenomas


Contributing organizations


Ministry reporting: Yes

Reporting Year: 2024

Preliminary JUFO rating: 1


Last updated on 2024-13-05 at 18:06