Commun Med (Lond). 2025 Nov 13. doi: 10.1038/s43856-025-01231-9. Online ahead of print.

ABSTRACT

BACKGROUND: Although germline testing for DNA mismatch repair (MMR) genes is routinely performed, clinical guidelines highlight evidence gaps due to limited populations and biases. We examined germline pathogenic variants of MMR genes (MLH1, MSH2, MSH6, and PMS2) in 112,927 unselected individuals from BioBank Japan.

METHODS: We analyzed 74,085 cancer patients with 23 cancer types and 38,842 controls matched by sex, age, and hospital area from BioBank Japan, collected between April 2003 and March 2018. Germline pathogenic variants in the coding regions and 2 bp flanking intronic sequences of MMR genes were identified using a multiplex PCR-based target sequencing method. We examined associations with cancer types and demographic characterization of the pathogenic variants, comparing findings to existing clinical guidelines.

RESULTS: Here we show 228 pathogenic variants identified in MMR genes, with pathogenic MSH6 variants most frequently observed in endometrial cancer and 12 other significant associations. Twelve other significant associations are noted across a broad range of odds ratios, whereas pancreatic cancer exhibits no such association. Pathogenic variant carriers are diagnosed up to 12.4 years earlier than non-carriers, and colorectal and gastric cancers are diagnosed up to 16.4 years later than indicated by the guidelines. Higher carrier frequencies are observed in patients with both colorectal and endometrial cancers (24.8%) and in those with endometrial cancer and a family history of endometrial (26.0%) or colorectal (16.1%) cancers.

CONCLUSIONS: This study provides critical insights for clinical guidelines on the associations between cancer types, age at diagnosis, and carrier frequency.

PMID:41258140 | DOI:10.1038/s43856-025-01231-9

Transl Oncol. 2025 Nov;61:102519. doi: 10.1016/j.tranon.2025.102519. Epub 2025 Sep 6.

ABSTRACT

Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA) from patient blood, have emerged as crucial and minimally invasive adjuncts to standard tissue-based testing. ctDNA testing enables the identification of actionable mutations for targeted therapy and can be routinely used when tissue samples are unavailable for genotyping. Compared to tissue-based testing, ctDNA testing has the advantages of capturing spatial or temporal genomic heterogeneity and facilitating repeated assessments. The utility of liquid biopsies extends to multiple clinical applications, including cancer diagnosis, treatment monitoring, and minimal residual disease (MRD) detection. Numerous clinical trials are currently evaluating treatment strategies using ctDNA testing. In particular, the implementation of adjuvant treatment escalation or de-escalation based on MRD detection could dramatically transform future approaches to solid tumor treatment. Various ctDNA assays have been developed, and it is important to understand their strengths and weaknesses for effective clinical applications. Furthermore, ctDNA testing faces several technical challenges, including low sensitivity in detecting copy number alterations and fusions, as well as the possibility of detecting mutations associated with clonal hematopoiesis of indeterminate potential. In this review, we comprehensively discuss the methodologies and recent advancements in cfDNA-based liquid biopsies for cancer patients, covering diagnosis, genomic profiling, and treatment monitoring. Furthermore, we explore clinical trial designs employing ctDNA testing and anticipate forthcoming changes in patient care.

PMID:40915174 | PMC:PMC12450568 | DOI:10.1016/j.tranon.2025.102519