Recent News 

This study examined the genomic impact of chemotherapy on 611 whole-genome-sequenced childhood cancer tumours from Canada, Australia, and the United States, with detailed records of every drug, dose, and treatment date. Post-therapy tumours carried nearly three times the number of mutational signatures and twice the overall mutation burden of treatment-naive tumours. Platinum-based therapies emerged as the most potent mutagens, responsible for the highest number of genomic variants in most patients. Remarkably, detectable platinum mutational signatures appeared in tumours as early as 91 days after the start of treatment, and more than one-third of platinum-treated patients showed these signatures within just 12 months. Patients whose tumours carried platinum signatures had significantly worse clinical outcomes and higher rates of treatment resistance. The findings provide a genomic roadmap of chemotherapy damage in childhood cancer, with implications for treatment de-escalation and early detection of resistant clones.

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This study re-examined mutational signature analysis of 802 microsatellite-stable colorectal cancers from the Mutographs project and uncovered a previously overlooked signature, SBS_D — now provisionally catalogued in COSMIC as SBS111. Originally dismissed as a combination of known signatures including SBS18 (linked to reactive oxygen species), the study demonstrates through analysis of 2,616 colorectal cancers across three independent cohorts that SBS_D is a genuinely distinct mutational process. Present in over half of DNA repair-proficient colorectal cancer samples, SBS_D appears preferentially in late-stage tumor evolution, suggesting it may arise from POLD1 proofreading errors and mismatch repair infidelity occurring late in cancer development. The work highlights the risks of over-decomposing novel signatures into known ones, and establishes SBS111 as a new entry in the catalogue of human mutational signatures.

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This study analyzed whole-genome sequences of 871 never smokers with lung cancer from 28 countries to uncover the mutagenic forces driving this understudied disease. Using mutational signature analysis, the team identified key geographic differences — EGFR mutations dominating in East Asia, KRAS in North America and Europe, and aristolochic acid exposure found almost exclusively in Taiwan, marking the first evidence of this carcinogen causing lung cancer. While secondhand smoke showed no direct mutational link, air pollution exhibited a clear dose-response effect, increasing mutation burden and TP53 mutations. The dominant signature, SBS40a of unknown cause, was strongly tied to EGFR-mutated tumours. This largest-ever genomic study of never-smoker lung cancer reveals a complex, geography-dependent mutational landscape and points to new environmental targets for prevention.

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This study analyzed whole-genome sequences of 981 colorectal cancers from 11 countries across 4 continents to map geographic and age-related differences in mutational processes. A key finding was that mutational signatures SBS88 and ID18 — caused by colibactin, a toxin produced by certain strains of E. coli — are 3.3 times more prevalent in early-onset colorectal cancer (diagnosed under age 40) compared to those over 70. Colibactin was also shown to directly drive mutations in the APC tumor suppressor gene, responsible for ~25% of APC driver indels — a critical early step in colorectal cancer development. The study reveals how bacteria, geography, and age interact to shape the mutational landscape of one of the world’s most common cancers.

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This study analyzed whole-genome sequences of 962 kidney cancers from 11 countries to identify hidden environmental causes behind global differences in kidney cancer rates. Using mutational signature analysis, the team uncovered distinct region-specific carcinogens — including aristolochic acid (prevalent in Romania, Serbia, and Thailand), an unknown mutagen dominant in Japan, and an unidentified signature linked to high-incidence regions in Central and Northern Europe. Notably, no mutational signature was found for obesity or hypertension, suggesting these known risk factors act through non-mutagenic mechanisms. The study highlights the potential of large-scale global cancer genomics to reveal previously unrecognized carcinogenic exposures affecting millions of people worldwide.

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Some cancers carry a DNA-repair defect called homologous recombination deficiency (HRD) that makes them especially responsive to platinum chemotherapy and PARP inhibitors, but testing for it usually requires specialized genomic testing that isn't available everywhere. We helped develop DeepHRD, an AI tool that predicts HRD status directly from routine tissue slides already produced in any pathology lab. In platinum-treated breast cancer patients, those the AI identified as HRD-positive had more than triple the progression-free survival of other patients, with similar benefits seen in ovarian cancer, and no difference on non-platinum treatments, showing the tool is capturing something biologically real. Compared with standard molecular testing, DeepHRD identified up to three times as many HRD-positive patients who could benefit from the right treatment, using tools pathology labs already have. 

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We developed a novel machine learning tool, SigProfilerExtractor, that allows extracting de novo mutational signatures from cancer genomic data. We demonstrated that SigProfilerExtractor outperforms 13 existing approaches, by conducting the largest benchmarking of bioinformatics tools for extracting mutational signatures using more than 80,000 synthetic cancer samples. Applying SigProfilerExtractor to more than 23,000 sequenced human cancers revealed novel insights about the processes leading to somatic mutation accumulation and tumorigenesis, including a novel mutational signature related to tobacco smoking mutagenesis in bladder cancer and normal bladder epithelium.

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As part of a large collaborative project, our lab co-led the development of a conceptual framework for examining the patterns of copy number alterations in human cancer. This conceptual framework allowed deriving the first reference set of copy number signatures across the spectrum of human neoplasia. The performed analysis revealed 21 distinct copy number signatures across 9,873 cancers representing 33 human cancer types. Moreover, for some copy number signatures, we were able to elucidate their biological mechanisms and to show their immediate clinical relevance. The reference set of copy number signatures was deposited on the COSMIC database and can be freely and easily utilized by other researchers as part of their omics studies. 

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Our analysis revealed that clustered mutations play a key role in driving cancer evolution and can be utilize as clinical biomarkers for predicting patient survival. Importantly, a class of clustered mutations, which we termed kyklonas (Greek for cyclone), were shown to be generated by the activity of APOBEC3 deaminases on extrachromosomal DNA, small circular pieces of DNA with a structure and replication pattern similar to that of a virus. APOBEC3 likely mistakes ecDNA as a virus and tries to eliminate it. But repeated mutagenic attacks to ecDNA result in clustered mutagenesis of the oncogenes it contains. Rather than eradicating the threat, this mutagenesis contributes to tumor evolution, promoting aggressive tumor behavior and treatment resistance. 

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As part of the global Mutographs project, we recruited patients from eight countries around the world with drastically different risk for developing esophageal squamous cell carcinoma. When we embarked on this study, we were looking for a genomic mutational signature which was only present or increased in areas where people have high risk for esophageal squamous cell carcinoma. The analysis of esophageal cancer genomes, using our advanced machine learning approaches, revealed an unexpected surprise - a common mutational process, driven by the APOBEC3 family of deaminases, is the ubiquitous culprit causing cancer in almost all patients in these eight countries. 

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As part of the global Scherlock-lung project, we investigated the molecular mechanisms by which people, who never smoked, get lung cancer. Our analysis revealed that the lung cancer genomes of never smokers are dramatically different when compared to the lung cancer genomes of tobacco smokers. Moreover, our examination revealed strong evidence for difference molecular subtypes within lung cancers of never smokers. These subtypes can be leveraged as a clinical utility for better managing and treating lung cancer in patients, who have never smoked.  

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We found that chronic inflammation can drive early, pre-cancerous blood stem cells to evolve and accumulate mutations faster. 

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As part of the international Pan-Cancer Analysis of Whole Genomes project, we helped produce the most comprehensive catalog yet of the mutational signatures found across human cancers. 

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Ludmil was named a 2019 Packard Fellow for Science and Engineering by the David and Lucile Packard Foundation, recognizing his work in biological sciences at UC San Diego.

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We contributed to work tracing the global spread of a transmissible cancer that has jumped between dogs for thousands of years.  

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Ludmil received a 2018 Sloan Research Fellowship from the Alfred P. Sloan Foundation for his work on mutational signatures.

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Ludmil was awarded the Genetics Society's 2018 Balfour Lecture in recognition of his contributions to understanding mutational signatures.

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As part of a collaborative study led by St. Jude Children's Research Hospital, we helped show that children and adults with cancer usually have different mutated genes driving their disease, underscoring the need to develop precision medicines designed specifically for pediatric cancer. 

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Popular Mechanics profiled our use of the Comet supercomputer at UC San Diego to identify mutational signatures across tumor samples from 22 countries, highlighting that our algorithm had found 90 signatures (with about 40 well understood at the time) and that our early work on the plant Aristolochia was later shown by another team to cause up to 80% of liver cancers in Taiwan. The piece also noted a newly awarded $30 million grant to analyze 5,000 patients in search of the causes behind the remaining unexplained signatures.

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We helped uncover the earliest mutational events in human development, revealing how mutations begin accumulating from the very first cell divisions of life. 

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Our lab was awarded a $25 million Cancer Research UK Grand Challenge grant to lead an international effort mapping the mutational fingerprints behind pancreatic, kidney, esophageal, and bowel cancers. As Ludmil put it at the time, "eight out of 10 cancers we cannot explain; we don't know what caused them." Working with the World Health Organization, UC San Francisco, the Wellcome Trust Sanger Institute, and King's College London, the team pulled patient data from more than 20 countries selected for their unusually high, well-documented rates of specific cancers, aiming to trace each cancer's distinctive mutational "fingerprint" back to its environmental or biological cause.

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