About

Peter Park, PhD, is a Professor of Biomedical Informatics at Harvard Medical School and serves as the director of its Bioinformatics and Integrative Genomics (BIG) PhD program. His research group specializes in the computational and statistical analysis of large-scale DNA sequencing data to understand genetic and epigenetic mechanisms related to disease processes. Originally trained in applied mathematics with a B.A. from Harvard and a Ph.D. from Caltech, he was introduced to molecular biology and genetics during his postdoctoral studies in biostatistics. His laboratory has developed several algorithms for identifying and interpreting genomic alterations in the human genome, especially those from cancer patients. His group has contributed significantly to numerous consortium projects such as The Cancer Genome Atlas (TCGA), Encyclopedia of DNA Elements (ENCODE), Brain Somatic Mosaicism Network, 4D Nucleome, and Somatic Mosaicism across Human Tissues (SMaHT). His work has been funded by prominent organizations including the National Institutes of Health, Cancer Research UK Grand Challenges, The Mark Foundation for Cancer Research, and others.

Research topics

• Biology
• Genetics
• Computational biology
• Evolutionary biology
• Statistics
• Cancer research
• Mathematics
• Virology

Selected publications

• Supplemental Materials

  Advances in Biology Laboratory Education · 2026-01-01

  articleSenior author
  PublisherDOI

• An integrated view of the structure and function of the human 4D nucleome

  Nature · 2025-12-17 · 19 citations

  articleOpen access

  to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

  PublisherDOI

• HER2DX in older patients with HER2-positive early breast cancer: extended follow-up from the RESPECT trial of trastuzumab ± chemotherapy

  UNC Libraries · 2025-11-14

  articleOpen access

  Older adults with HER2-positive early breast cancer are underrepresented in clinical trials, and the benefit of chemotherapy in this population remains uncertain. We evaluated the HER2DX genomic assay within the randomized RESPECT trial (NCT01104935), which compared adjuvant trastuzumab with or without chemotherapy in patients aged 70–80 years. In this prespecified translational analysis (Trans-RESPECT), HER2DX scores were available for 154 patients. The HER2DX risk score classified 74.0% as low risk and 26.0% as high risk. Ten-year relapse-free and overall survival were higher in the low-risk group. HER2DX remained independently associated with overall survival in multivariable analysis. The HER2DX immune, luminal, and proliferation signatures that compose the risk score were also prognostic. While the HER2DX pCR score was not prognostic overall, exploratory subgroup analyses suggested a potential survival benefit from chemotherapy in the pCR-high group. HER2DX offers prognostic value and may guide chemotherapy use in older patients with HER2-positive early breast cancer. Clinical Trial Information NCT01104935In the RESPECT randomized trial (trastuzumab ± chemotherapy) in women aged 70–80 with HER2-positive early breast cancer, tumor/immune profiling with HER2DX stratified prognosis and helped identify when chemotherapy may be avoided.

  PublisherDOI

• Supplementary Figures 1-15 from Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA

  2025-12-11

  articleOpen access

  <p>Supplementary figures provide additional details on the genomic landscape of MPNST and interesting cases within the cohort.</p>

  PublisherOA PDFDOI

• Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation

  Nature Genetics · 2025-12-18 · 2 citations

  articleOpen access

  Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.

  PublisherDOI

• A comprehensive view of somatic mosaicism by single-cell DNA analysis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-03 · 4 citations

  preprintOpen access

  Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues-insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

  PublisherOA PDFDOI

• HER2DX in older patients with HER2-positive early breast cancer: extended follow-up from the RESPECT trial of trastuzumab ± chemotherapy

  Nature Communications · 2025-11-04 · 2 citations

  articleOpen access

  Older adults with HER2-positive early breast cancer are underrepresented in clinical trials, and the benefit of chemotherapy in this population remains uncertain. We evaluated the HER2DX genomic assay within the randomized RESPECT trial (NCT01104935), which compared adjuvant trastuzumab with or without chemotherapy in patients aged 70-80 years. In this prespecified translational analysis (Trans-RESPECT), HER2DX scores were available for 154 patients. The HER2DX risk score classified 74.0% as low risk and 26.0% as high risk. Ten-year relapse-free and overall survival were higher in the low-risk group. HER2DX remained independently associated with overall survival in multivariable analysis. The HER2DX immune, luminal, and proliferation signatures that compose the risk score were also prognostic. While the HER2DX pCR score was not prognostic overall, exploratory subgroup analyses suggested a potential survival benefit from chemotherapy in the pCR-high group. HER2DX offers prognostic value and may guide chemotherapy use in older patients with HER2-positive early breast cancer. Clinical Trial Information NCT01104935.

  PublisherOA PDFDOI

• Comprehensive benchmarking of somatic single-nucleotide variant and indel detection at ultra-low allele fractions using short- and long-read data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Mosaic mutations in normal tissues occur at low variant allele fractions (VAFs), complicating detection. To benchmark strategies, the SMaHT Network created a cell-line mixture (1:49) and produced ultra-deep whole-genome sequencing using short and long reads (five centers, 180-500× each). We assembled a reference of 44,008 mosaic SNVs and 2,059 Indels, cross-validation between platforms to expose limits of short-read analysis. We also partitioned the genome by mappability to examine the impact of genomic context, added a negative reference set, and accounted for culture-derived mutations. When seven institutions applied eleven algorithms to mixture data, call sets were largely discordant across tools and replicates, partly reflecting stochastic presence of low-VAF mutations in biological replicants. For >2% VAF SNVs, sensitivity and precision approached ~80% at ≥300×, with little gain from additional sequencing. This work provides a comprehensive framework for reliable detection of low-VAF mutations in non-cancer tissues and a valuable resource for the community.

  PublisherOA PDFDOI

• Supplementary Figure S2 from Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma

  2025-12-17

  articleOpen access

  <p>Supplementary Figure S2: A. Counts of small deletions (<30kb) are compared in Sig3+ and Sig3- LMS tumors (analyzed by OncoPanel v3 and v 3.1, n=166). B. Counts of small deletions (<30kb) are significantly higher in tumors with deleterious alterations in POLH, POLD1, FANCM or XRCC1, all of which are implicated in DNA double strand break repair during different phases of the cell cycle (**** = p < 0.0001; n.s.= not significant)</p>

  PublisherDOI

• A recurrent sequencing artifact on Illumina sequencers with two-color fluorescent dye chemistry and its impact on somatic variant detection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-29 · 1 citations

  preprintOpen accessSenior authorCorresponding

  BACKGROUND: The sequencing-by-synthesis technology by Illumina, Inc. enables efficient and scalable readouts of mutations from genomic data. To enhance sequencing speed and efficiency, Illumina has shifted from the four-color base calling chemistry of the HiSeq series to a two-color fluorescent dye chemistry in the NovaSeq series. Benchmarking sequencing artifacts due to biases in the newer chemistry is important to evaluate the quality of identified mutations. RESULTS: We re-analyze a series of whole-genome sequencing experiments in which the same samples were sequenced on the NovaSeq 6000 (two-color) and HiSeq X10 (four-color) platforms by independent groups. In several samples, we observe a higher frequency of T-to-G and A-to-C putative substitutions ("T > G") at the read level for NovaSeq 6000 versus HiSeq X10. As the per-base error rate is still low, the artifactual substitutions have a negligible effect in identifying germline or high variant allele frequency (VAF) somatic mutations. However, such errors can confound the detection of low-VAF somatic variants in high-depth sequencing samples, particularly in studies of mosaic mutations in normal tissues, where variants have low read support and are called without a matched normal. The artifactual T > G variant calls disproportionately occur at NT[TG] trinucleotides, and we leverage this observation to bioinformatically reduce the T > G excess in somatic mutation callsets. CONCLUSIONS: We identified a recurrent artifact specific to the Illumina two-color chemistry platform on the NovaSeq 6000 with the potential to contaminate low-VAF somatic mutation calls. Thus, an unexpected enrichment of T > G mutations in mosaicism studies warrants caution.

  PublisherOA PDFDOI

Recent grants

• 1/2-Somatic mosaicism and autism spectrum disorder

  NIH · $1.8M · 2015–2020

• NIH Grant RC1HG005482

  NIH · $773k · 2012

• 4D Nucleome Network Data Coordination and Integration Center

  NIH · $21.9M · 2015–2026

• Mutational signature analysis: methods and applications to the clinic

  NIH · $453k · 2022–2027

• 1/2-Somatic mosaicism and autism spectrum disorder

  NIH · $7.4M · 2015–2021

Frequent coauthors

• Christopher A. Walsh

  Mount Sinai Hospital

  187 shared

• Peter V. Kharchenko

  Harvard University

  179 shared

• Eunjung Alice Lee

  Broad Institute

  178 shared

• Rory Johnson

  University Hospital of Bern

  169 shared

• Michael Tolstorukov

  168 shared

• L. Sylvia

  Mirai Hospital

  164 shared

• Joshua M. Stuart

  University of California, Santa Cruz

  163 shared

• Lars Feuerbach

  German Cancer Research Center

  159 shared

Labs

• Park LabPI