# Quantifying rate-limiting genetic variation in breast and ovarian tumourigenesis

## TL;DR

This study identifies chromosomal deletions as key events in the early stages of breast and ovarian cancer, suggesting they are more important than single-letter DNA changes.

## Contribution

The study introduces a statistical framework to quantify the minimal number and type of genetic events required for cancer initiation.

## Key findings

- Deletions, not single-letter DNA changes, are likely the rate-limiting events in tumourigenesis.
- One to three deletions are sufficient to initiate tumourigenesis, while single-letter changes alone cannot explain cancer incidence.
- BRCA1/2 carriers and non-carriers share similar deletion profiles, but carriers accumulate them faster.

## Abstract

The number and type of genetic alterations required to initiate breast and ovarian cancer remain unclear. While germline BRCA1/2 carriers show markedly elevated cancer risk, it is uncertain whether point mutations or copy number alterations constitute the rate-limiting events of tumourigenesis.

We developed a statistical framework extending prior incidence–mutation models to estimate the minimal number and type of driver events required for cancer initiation. Somatic mutation and copy-number data from >3000 breast and ovarian cancers in TCGA and METABRIC were compared between germline BRCA1/2 carriers and non-carriers matched on subtypes. Results were validated through analyses of evolutionary timing data, as well as single-cell whole genome sequencing (scWGS) data of genetically-engineered and patient-derived cancer/pre-cancerous cells.

Deletions, rather than single-nucleotide variants (SNVs), emerged as the likely rate-limiting events. Modeling indicated that 1–3 deletions are sufficient to initiate tumourigenesis, whereas SNVs alone could not explain observed incidence ratios. BRCA1/2-driven and sporadic tumours converged on similar deletion profiles, including early recurrent deletions of chromosomes 13q and 17, though carriers accumulated them more rapidly.

Deletion-associated chromosomal instability likely represents the central trigger for breast and ovarian cancer initiation. These results explain why certain somatic driver mutations detected in normal tissues may not predict malignant progression, and that early detection strategies should instead prioritize testing deletions as potential biomarkers.

10.13039/100000002NIH/10.13039/100000054NCI (P30CA016042; 1U01CA214194-01), NIH NIGMS (R35GM138113, 2R35GM138113), ACS (RSG-22-115-01-DMC), CIHR Vanier Fellowship, and the Francis Crick Institute with core funding from Cancer Research UK, UK 10.13039/501100000265Medical Research Council, and 10.13039/100010269Wellcome Trust.