RFP5. Genetic ancestry correlates with differences in somatic mutations in a real-world clinical breast cancer sequencing cohort

Friday, March 6, 2026

4:45 PM - 4:52 PM MST

Location: 106A-C

Primary Presenter(s)

Jacquelyn Dillon, MD (she/her/hers)

Breast Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
NY, New York, United States

Slides

Co-Author(s)

XB

Xuechun Bai, MA

Computational Oncology, Department of Epidemiology and Biostatistics
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Yashasvini Sampathkumar, MD (she/her/hers)

Breast Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
Montclair, New Jersey, United States
RK

Risa Kiernan, DO

Breast Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
New York, New York, United States
RJ

Robert James, MD

Breast Service, Department of Surgery
Memorial Sloan-Kettering Cancer Center
NY, New York, United States
MW

Michele Waters, PhD

Computational Oncology, Department of Epidemiology and Biostatistics
Memorial Sloan Kettering Cancer Center
New York, New York, United States
JC

Jian Carrot-Zhang, PhD

Clinical Genetics, Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Monica Morrow, MD (she/her/hers)

Chief, Breast Service, Department of Surgery; Anne Burnett Windfohr Chair of Clinical Oncology; Vice President, Women in Science and Medicine, MSKCC; Professor of Surgery, Weill Cornell Medical College of Cornell University
Memorial Sloan Kettering Cancer Center
New York, New York, United States

Primary Author(s)

NG

Neha Goel, MD, MPH

Breast Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
New York, New York, United States

Introduction: Self-reported race and ethnicity, a sociopolitical construct reflecting social and ancestral factors, is associated with differences in breast cancer (BC) tumor characteristics and somatic mutations, as well as disparate outcomes. Ancestral origin encompasses distinct genomic architecture shaped by evolution, and accurate genetic ancestry inference is critical for identifying genetic contributors to cancer disparities. Prior studies evaluating associations between genetic ancestry and somatic mutations have included few patients of non-European ancestry, limiting generalizability and novel discovery of actionable mutations in diverse populations. This study aims to assess associations between genetic ancestry and somatic differences in a real-world BC sequencing cohort.

Methods: We analyzed data from 7374 patients (10,118 samples) who underwent targeted sequencing as part of routine clinical care at a tertiary cancer center. 1926 samples were excluded. ADMIXTURE sequencing software estimated proportions of AFR (African), EUR (European), EAS (East Asian), NAM (Native American), and SAS (South Asian) ancestry. We assigned ancestry labels if any ancestral fraction was ≥ 0.8 or an admixed label if all populations were < 0.8. Sequencing data were linked to clinical characteristics, and logistic regression analyzed associations between genetic ancestry, tumor characteristics, and somatic mutations.

Results: Median age was 60 years. Most patients (57.5%) had stage 1-3 BC, while 23.0% had stage 4, and 19.4% had unknown stage (Table). 60.1% of patients had ER+/HER2- disease. EUR ancestry was most prevalent (61.0%), followed by admixed (13.0%), AFR (6.8%), EAS (4.6%), SAS (2.1%), and NAM (0.4%). On multivariable analysis adjusting for BC stage and subtype, significant ancestry-associated somatic mutations were identified. AFR was associated with higher odds of TP53 and GATA3 mutations, and lower odds of ERBB2, PIK3CA, CDH1, and TBX3 mutations. EAS and NAM were associated with lower odds of CDH1 mutations. NAM was associated with higher odds of PTEN and STK11 mutations.

Conclusions: We identified both known and novel associations between diverse genetic ancestries and somatic mutations in a real-world BC cohort. Notably, AFR ancestry was associated with lower odds of actionable mutations (ERBB2 and PIK3CA). As precision oncology expands, ensuring equitable sequencing access across diverse populations by incorporating targeted clinical panels into routine diagnostic workflows is essential to uncover actionable mutations in diverse populations.

Learning Objectives:

Recognize the significant association between genetic ancestry and somatic mutations in breast cancer patients.
Recognize that actionable mutations are less frequently observed in patients of African genetic ancestry.
Recognize the importance of somatic sequencing in diverse patient populations to facilitate continued discovery of actionable mutations.