Differential causative effects of germline pathogenic variants in MUTYH and PALB2 in a patient with colorectal polyposis and breast cancer

Tumor mutational signatures to dissect the respective contributions of MUTYH (BERd) and PALB2 (HRD) in two distinct tumors from a single MINAS patient

In a patient with colorectal polyposis and breast cancer carrying biallelic pathogenic MUTYH variants and a heterozygous pathogenic PALB2 variant, tumor mutational signature analysis differentiates each gene's contribution. The colorectal polyp shows predominantly BER-deficiency (MUTYH) signatures without HRD; the breast tumor shows both BER and HRD signatures (SBS3, ID6, elevated HRD score) despite absent detectable somatic PALB2 second hit. This case demonstrates that mutational signatures can decompose CSG contributions in the MINAS framework.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Using mutational signatures to dissect the contributions of multiple predisposition genes in a single MINAS patient is elegant and potentially transformative for genetic counseling. HRD detection in the breast tumor despite absent PALB2 second hit raises the haploinsufficiency question, with direct PARP inhibitor eligibility implications. Single-case result: requires confirmation in a larger cohort.

Clinical impact: 2/3 · Evidence strength: 1/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 0/1 · Preprint: -1 → Total: 4/10