RESUMEN
We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Carcinoma/genética , Segregación Cromosómica/genética , Codón sin Sentido/genética , Exoma/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Análisis de Secuencia de ADN , Proteínas Supresoras de Tumor/genética , Alelos , Secuencia de Bases , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Reproducibilidad de los ResultadosRESUMEN
IMPORTANCE: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. OBJECTIVE: To classify PDAC according to distinct mutational processes, and explore their clinical significance. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. MAIN OUTCOMES AND MEASURES: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. RESULTS: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. CONCLUSIONS AND RELEVANCE: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Mutación , Neoplasias Pancreáticas/genética , Anciano , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/metabolismo , Carcinoma Ductal Pancreático/inmunología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación de la Incompatibilidad de ADN/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , Genes BRCA1/fisiología , Genes BRCA2/fisiología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Neoplasias Pancreáticas/inmunología , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Proteínas Supresoras de Tumor/genética , Neoplasias PancreáticasRESUMEN
The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.