Evidence map›Paper›PMID 41724111›Full record

ArticleEBioMedicine2026

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

Kathleen E Houlahan, Mahad Bihie, Yves Greatti, Julián Grandvallet Contreras, Daniel J Fulop, Gonzalo Lopez, Marc Williams, Hsin-Hsiung Huang, Peter Van Loo, Paul C Boutros and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Kathleen E HoulahanDepartment of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Vector Institute, Toronto, Canada; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
Mahad BihieDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Yves GreattiJohns Hopkins University, Baltimore, USA.
Julián Grandvallet ContrerasDepartment of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Daniel J FulopDepartment of Genetics and Genomic Sciences, Department of Artificial Intelligence and Human Health, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Gonzalo LopezDepartment of Genetics and Genomic Sciences, Department of Artificial Intelligence and Human Health, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Marc WilliamsMemorial Sloan Kettering Cancer Center, New York, USA.
Hsin-Hsiung HuangDepartment of Statistics, University of Central Florida, Orlando, FL, USA.
Peter Van LooThe Francis Crick Institute, London, UK; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Paul C BoutrosDepartment of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Vector Institute, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: pboutros@sbpdiscovery.org.
Kuan-Lin HuangDepartment of Genetics and Genomic Sciences, Department of Artificial Intelligence and Human Health, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: kuan-lin.huang@mssm.edu.

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI SELWYN M VICKERS · 1985 to 2026
$347.4M
Integrative Approaches for Identifying Causal Gene-Cell Type Pairs of Complex DiseaseR35GM138113 · NIGMS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Kuan-lin Huang · 2020 to 2026
$3.0M
NCI NIH HHS P30 CA008748NIGMS NIH HHS R35 GM138113
6 · The paper itself

Abstract

backgroundThe 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.

methodsWe 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.

findingsDeletions, 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.

interpretationDeletion-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.

fundingNIH/NCI (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 Medical Research Council, and Wellcome Trust.

Indexed as

Breast NeoplasmsCarcinogenesisGenetic VariationOvarian NeoplasmsBRCA2 ProteinDNA Copy Number VariationsFemaleGenetic Predisposition to DiseaseGerm-Line MutationHumansMutationPolymorphism, Single NucleotideBRCA2 ProteinBRCA1BRCA2Breast cancerGermline predispositionOvarian cancerTumourigenesis

Identifiers

PMID41724111
PMCPMC12945530

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.