Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Alisa Olkinuora; Satu Mäki-Nevala; Sanjeevi Ukwattage; Ari Ristimäki; Maarit Ahtiainen; Jukka-Pekka Mecklin; Päivi Peltomäki

doi:10.3389/fonc.2024.1378392

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Front Oncol. 2024 Apr 25:14:1378392. doi: 10.3389/fonc.2024.1378392. eCollection 2024.

Authors

Alisa Olkinuora¹, Satu Mäki-Nevala¹, Sanjeevi Ukwattage¹, Ari Ristimäki^{2

3}, Maarit Ahtiainen⁴, Jukka-Pekka Mecklin^{5

6}, Päivi Peltomäki^{1

7}

Affiliations

¹ Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
² Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, HUS, Helsinki, Finland.
³ Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Department of Pathology, Wellbeing Services County of Central Finland, Jyväskylä, Finland.
⁵ Department of Education and Science, Nova Hospital, Central Finland Health Care District, Jyväskylä, Finland.
⁶ Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁷ HUSLAB Laboratory of Genetics, HUS Diagnostic Center, HUS, Helsinki University Hospital, Helsinki, Finland.

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; RNF43; exome sequencing; multiple adenomas; panel sequencing.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from Biomedicum Helsinki Foundation (to AO); the Jane and Aatos Erkko Foundation (to PP); the Academy of Finland (grant number 330606 to PP, and 331284 to SM-N); Cancer Foundation Finland sr (to AO, PP, and AR); the Finska Läkaresällskapet (to AR); Medicinska Understödsföreningen Liv & Hälsa (to AR); Helsinki University Central Hospital Research Funds (to AR); and the Sigrid Juselius Foundation (to PP and AR).