# Mutational landscape of normal breast tissues adjacent to invasive breast cancer

## TL;DR

This study finds that normal breast tissues near breast cancer often share mutations with the cancer, suggesting germline variants may drive cancer risk.

## Contribution

The study reveals that germline polymorphisms in cancer-related genes contribute to shared mutations in cancer-adjacent normal tissues and tumors.

## Key findings

- Cancer-adjacent normal breast tissues contain somatic mutations also found in tumors.
- Germline polymorphisms in cancer hallmark pathways contribute to patient-specific mutation patterns.
- Shared mutations suggest phenotypic convergence and gradual malignant transformation.

## Abstract

Individuals with a history of breast cancer are at increased risk of developing a new breast cancer during their lifetime. Rare but high-impact somatic mutations in normal breast tissues may contribute to malignant transformation. We analyze mutations in cancer-relevant pathways across matched samples of peripheral blood, cancer-adjacent normal breast, and breast cancer from patients diagnosed before 50 years of age who carry no germline mutations in cancer-predisposing genes. Gene- and pathway-level mutation profiles and single-base substitution (SBS) signatures are compared between tissue types in two independent cohorts (Yale, n = 24; TCGA, n = 17). Cancer-adjacent normal breast tissue contains multiple acquired somatic mutations that persist in tumors. Most variants are shared across tissue types from the same individual, indicating strong germline influence. The substantial germline contribution to alterations through common and rare polymorphisms in cancer hallmark pathways supports a model of cancer risk based on the collective impact of variants in cancer-related genes.

•BC patients harbor many protein-altering germline variants in cancer-relevant genes•Cancer-adjacent normal breast tissues carry many of the same mutations found in cancer•A patient-specific pattern of pathway-level mutations indicates phenotypic convergence•Vast gHFIs not linked to cancer risk suggest context-dependent biological effect

BC patients harbor many protein-altering germline variants in cancer-relevant genes

Cancer-adjacent normal breast tissues carry many of the same mutations found in cancer

A patient-specific pattern of pathway-level mutations indicates phenotypic convergence

Vast gHFIs not linked to cancer risk suggest context-dependent biological effect

Suwalska et al. show that cancer-adjacent normal breast tissues share genomic alterations with cancer, and many changes in cancer-relevant genes arise from specific combinations of germline polymorphisms. This supports gradual mutation-driven malignant transformation of normal cells and suggests context-dependent co-oncogenic function for common and rare germline polymorphisms.