RESUMEN
Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
RESUMEN
We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Colorrectales , Neoplasias de la Úvea , Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Endodesoxirribonucleasas/genética , Predisposición Genética a la Enfermedad , Células Germinativas/patología , Mutación de Línea Germinal/genética , Humanos , Neoplasias de la Úvea/genéticaRESUMEN
Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8+ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8+ T cell responses relatively infrequently during infection, CD8+ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Antígenos Virales/genética , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Estudios de Cohortes , Reacciones Cruzadas/inmunología , Conjuntos de Datos como Asunto , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Evasión Inmune , Péptidos/genética , Péptidos/inmunología , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/inmunología , Empalme del ARN/inmunología , ARN Viral/sangre , ARN Viral/genética , ARN Viral/aislamiento & purificación , RNA-Seq , Proteínas Virales/genética , Proteínas Virales/inmunología , Proteínas Virales/metabolismoRESUMEN
In small scale societies, lethal attacks on another individual usually invite revenge by the victim's family. We might expect those who perpetrate such attacks to do so only when their own support network (mainly family) is larger than that of the potential victim so as to minimise the risk of retaliation. Using data from Icelandic family sagas, we show that this prediction holds whether we consider biological kin or affinal kin (in-laws): on average, killers had twice as many relatives as their victims. These findings reinforce the importance of kin as a source of implicit protection even when they are not physically present. The results also support Hughes' (1988) claim that affines are biological kin because of the shared genetic interests they have in the offspring generation.
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Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.
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Carcinoma de Células Renales , Neoplasias Renales , Mutación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Secuenciación Completa del Genoma , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/genética , Neoplasias Renales/terapia , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Pronóstico , Masculino , Femenino , Variaciones en el Número de Copia de ADN , Persona de Mediana Edad , Epigénesis Genética , Anciano , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodosRESUMEN
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing the most detailed somatic mutational landscape to date. We identify new driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for drug repurposing. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The twin observations that higher T-cell infiltration is associated with better outcome and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.
RESUMEN
For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Monocitos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , InmunoterapiaRESUMEN
Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding.
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Endorfinas/metabolismo , Risa , Umbral del Dolor/psicología , Conducta Social , Femenino , Humanos , MasculinoRESUMEN
Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives.