Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

• MeSH
• alely MeSH
• antigeny CD38 * genetika   imunologie   antagonisté a inhibitory   MeSH
• chemorezistence * genetika   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• membránové glykoproteiny * genetika   imunologie   MeSH
• mnohočetný myelom * genetika   imunologie   farmakoterapie   patologie   MeSH
• monoklonální protilátky * terapeutické užití   farmakologie   MeSH
• únik nádoru z imunitní kontroly * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD38 * MeSH
• CD38 protein, human MeSH Prohlížeč
• daratumumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• isatuximab MeSH Prohlížeč
• membránové glykoproteiny * MeSH
• monoklonální protilátky * MeSH

Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers1,2 and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies3-5. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause6, contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid7,8, was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking9, and a 76% increase in the clock-like10 signature SBS5. A positive dose-response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

• MeSH
• adenokarcinom genetika   MeSH
• erbB receptory genetika   MeSH
• genom lidský * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * genetika   MeSH
• mutageneze * genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory plic * genetika   patologie   MeSH
• nekuřáci * MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři MeSH
• znečištění ovzduší škodlivé účinky   MeSH
• znečištění tabákovým kouřem škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• KRAS protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny p21(ras) MeSH
• TP53 protein, human MeSH Prohlížeč
• znečištění tabákovým kouřem MeSH

Incidence rates of colorectal cancer vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries2-5. The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

• MeSH
• dospělí MeSH
• incidence MeSH
• kolorektální nádory * genetika   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• mutace INDEL genetika   MeSH
• mutace * genetika   MeSH
• mutační rychlost MeSH
• mutageny metabolismus   MeSH
• peptidy metabolismus   MeSH
• polyketidy metabolismus   MeSH
• senioři MeSH
• věk při počátku nemoci MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Argentina epidemiologie   MeSH
• Brazílie epidemiologie   MeSH
• Kolumbie epidemiologie   MeSH
• Rusko epidemiologie   MeSH
• Thajsko epidemiologie   MeSH
• Názvy látek
• colibactin MeSH Prohlížeč
• mutageny MeSH
• peptidy MeSH
• polyketidy MeSH

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). We explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC samples from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and alcohol-related signatures, indicating a combined effect of these exposures. Tobacco smoking was associated with differences in the mutational spectra, repertoire of driver mutations in cancer genes and patterns of copy number change. Our results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

• MeSH
• kouření tabáku * škodlivé účinky   MeSH
• kouření škodlivé účinky   MeSH
• lidé MeSH
• mutace MeSH
• mutageneze * genetika   MeSH
• nádory hlavy a krku * genetika   etiologie   epidemiologie   MeSH
• sekvenování celého genomu MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Reactivated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

• MeSH
• genom lidský genetika   MeSH
• genomika MeSH
• hypertenze epidemiologie   MeSH
• incidence MeSH
• karcinom z renálních buněk * genetika   epidemiologie   chemicky indukované   MeSH
• kouření tabáku škodlivé účinky   genetika   MeSH
• kyseliny aristolochové škodlivé účinky   MeSH
• lidé MeSH
• mutace * MeSH
• mutageny * škodlivé účinky   MeSH
• nádory ledvin * genetika   epidemiologie   chemicky indukované   MeSH
• obezita epidemiologie   MeSH
• rizikové faktory MeSH
• vystavení vlivu životního prostředí * škodlivé účinky   analýza   MeSH
• zeměpis * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Japonsko epidemiologie   MeSH
• Rumunsko epidemiologie   MeSH
• Srbsko epidemiologie   MeSH
• Thajsko epidemiologie   MeSH
• Názvy látek
• kyseliny aristolochové MeSH
• mutageny * MeSH

The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.

• MeSH
• benchmarking * MeSH
• datové soubory jako téma MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA normy   MeSH
• nádorové buněčné linie MeSH
• nádory prsu genetika   MeSH
• referenční standardy MeSH
• reprodukovatelnost výsledků MeSH
• sekvenování celého genomu normy   MeSH
• vysoce účinné nukleotidové sekvenování normy   MeSH
• zárodečné buňky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.

• MeSH
• chemorezistence MeSH
• imunoterapie MeSH
• individualizovaná medicína * MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• metastázy nádorů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové biomarkery analýza   MeSH
• nádorové kmenové buňky fyziologie   MeSH
• nádory patologie   terapie   MeSH
• xenogenní modely - testy protinádorové aktivity * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• nádorové biomarkery MeSH