Sandra Perdomo

The incidence distribution of esophageal adenocarcinoma (EAC) and gastroesophageal junction (GEJ) cancers presents important geographic variations, yet the causes of these differences remain unclear. We analyzed 520 whole genomes from EAC/GEJ tumors across eight countries to examine the mutational forces shaping these cancers and their geographic variation. The mutational landscape was highly similar between EAC and GEJ tumors, and was dominated by signatures SBS17a/b, previously associated with reflux in EAC/GEJ. SBS17a/b were linked to obesity in EAC, supporting an indirect role in exacerbating reflux-mediated mutagenesis. Other established risk factors, such as tobacco smoking, did not yield a direct mutational footprint, pointing to non-mutagenic effects in EAC/GEJ. Nonetheless, geographic differences were present, with signatures related to endogenous cellular functions enriched in high-incidence populations. These findings provide new insights into the shared mutational forces that shape EAC and GEJ, as well as their geographic distribution.

Approximately half of all pancreatic cancers cannot be explained by known risk factors. Here we present the results of mutational signature analysis in 495 cases of pancreatic cancer from nine countries to explore whether there are previously unknown mutagenic exposures acting on pancreatic cancer genomes. The mutational signature landscape was consistent between countries. We identified one signature not previously found in pancreatic cancer, SBS111, which does not have a confirmed aetiology but is present in >99% of cases and contributes on average 26% of the total mutation burden. No evidence was found for mutational signatures known to be caused by exogenous exposures, nor was any mutational signature capable of explaining differences in incidence rates between countries. These results suggest that the unexplained causes of pancreatic cancer are unlikely to be strongly mutagenic and that non-mutagenic mechanisms may have a prominent role in explaining pancreatic cancer incidence.

Background: Tobacco, alcohol, and human papillomavirus (HPV) are major risk factors for oral cavity and oropharyngeal cancers, yet their specific contributions to the tumor molecular landscape remain incompletely understood. Methods: We analyzed somatic alterations in 1086 tumors (606 oral cavity cancers and 480 oropharyngeal cancers, including 287 HPV-positive oropharyngeal cancers) profiled with a 1109-gene panel and evaluated their associations with exposures. Results: PIK3CA alterations were widespread but context specific: HPV-positive oropharyngeal cancers featured APOBEC-driven mutations and co-occurrence of FGFR3 mutations in a subset of cases, while HPV-negative oropharyngeal cancers and oral cavity cancers were marked by 3q26/28 (PIK3CA/TP63/SOX2) amplifications. TP53 was the most frequently mutated gene in HPV-negative tumors, with strong enrichment among smokers in HPV-negative oropharyngeal cancers, whereas TP53 mutation frequencies in oral cavity cancers were consistently high, regardless of smoking status. CCND1 amplifications were largely restricted to HPV-negative tumors and were most frequent in individuals reporting combined tobacco and alcohol use. This combined effect was replicated in The Cancer Genome Atlas oral cavity cancer–oropharyngeal cancer cohort and mirrored at the transcriptomic level, where CCND1 messenger RNA expression was highest in dual tobacco-alcohol users. Within oral cavity cancers, characterization of 1 of the largest cohorts of tumors from never smoker–never drinkers to date (n = 100) showed that patients were more likely to be female and to exhibit enrichment for FAT1 and CASP8 mutations compared with tumors from ever smoker–ever drinkers (n = 353). Conclusions: Together, these findings define distinct, exposure-driven patterns of somatic alterations by subsite and HPV status and provide a molecular framework that may inform etiological-based risk stratification in head and neck cancer.

Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.

Mutational epidemiology integrates genomic techniques with large-scale population studies to uncover new causes of cancer. This approach goes beyond traditional epidemiology by analyzing the patterns of somatic mutations in cancer cells to identify specific mutational signatures that serve as a historical record of an individual’s past mutagenic exposures. The field is also expanding to study mutational landscapes in normal tissues and precancerous lesions to understand the earliest stages of carcinogenesis. Initial studies are exploring how factors like certain mutagenic bacteria and air pollution can act as mutagens or promoters, influencing the selection and expansion of preexisting mutated clones. Ultimately, the goal is to use this evidence to uncover new and potentially preventive causes of cancer, understand differences and over time changes in incidence of certain cancers and develop tailored prevention strategies and public health policies.

Objetivo: El cáncer de cabeza y cuello es el sexto tipo de cáncer más diagnosticado en el mundo. En América Latina y, en particular, en Argentina, la mayoría de los casos se detectan en estadios avanzados, lo que influye significativamente en su evolución y pronóstico. El objetivo de este taller de consenso fue identificar las barreras y oportunidades del sistema de salud en el proceso de diagnóstico del cáncer de cabeza y cuello para diseñar y proponer estrategias interinstitucionales e interdisciplinarias superadoras. Método: Se desarrolló un taller participativo con actores del sistema de salud de Córdoba, Argentina, en el marco del Programa de Prevención del Cáncer Bucal. Se utilizaron dinámicas de trabajo grupal y análisis de consensos sobre barreras, oportunidades y estrategias. Resultados: Se identificaron barreras estructurales en el acceso a la salud, la financiación, la centralización de servicios y la falta de acciones interdisciplinarias. Se propusieron estrategias para fortalecer las consultas odontológicas, optimizar los circuitos de derivación, fomentar redes interprofesionales y diseñar acciones específicas para poblaciones vulnerables. Conclusiones: Optimizar el diagnóstico temprano del cáncer de cabeza y cuello demanda un enfoque interinstitucional e interprofesional que integre estrategias de prevención, educación, redes de atención y fortalecimiento del sistema sanitario con el fin de reducir las inequidades en salud. Palabras clave: Cáncer de cabeza y cuello, diagnóstico temprano, inequidades en salud, prevención, promoción de la salud, redes de atención.

Supplementary Table S1 shows results of univariate analysis for 77 chronically elevated serum alanine aminotransferase (cALT)-defined nonalcoholic fatty liver disease SNPs in the Pancreatic Cancer Cohort Consortium (PanScan) data

Supplementary Table S2 shows results of univariate analysis for 22 imaging-defined nonalcoholic fatty liver disease SNPs in the PanScan sample

Supplementary Table S3 shows results of univariate analysis for 36 biopsy-confirmed nonalcoholic fatty liver disease SNPs in the PanScan sample