RESUMO
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
Assuntos
Análise Mutacional de DNA , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Reparo do DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Marcadores Genéticos/genética , Instabilidade Genômica/genética , Genótipo , Humanos , Camundongos , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/tratamento farmacológico , Platina/farmacologia , Mutação Puntual/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The purpose of this study was to determine the distribution of and potential significance of laminin 332 (LM332) in breast cancer. Specimens from a population-based cohort (Nâ¯=â¯297) from 1994 to 1995 were stained for estrogen receptor (ER), progesterone receptor (PgR), HER2 and the LM332 ß3 chain. Seventy-five tumors were LM332-positive and 222 were negative. LM332 ß3 stained 16.0% of ER and/or PgR-positive tumors and 73.2% of triple-negative breast cancers (TNBC). Immunoblotting revealed LM332 in TNBC and HER2-positive samples, but not in an ER-positive breast carcinoma or a phyllodes tumor. After 20 years, 172 patients were alive, 43 had died of breast cancer and 82 of other causes. Patients with LM332-positive tumors had significantly worse 5 (Pâ¯<â¯.0001) and 10-year (Pâ¯<â¯.05) overall and breast cancer specific survival. Among patients with LM332 ß3-expressing and ER/PgR-negative carcinomas, 10-year survival was significantly reduced (Pâ¯<â¯.0450). In a multivariate analysis LM332-positive patients had significant hazard ratios of 3.9 with 95% confidence intervals (CI) of 2.0-7.7 and 2.2 with 95% CI of 1.3-3.8 for 5 and 10-year overall survival, respectively. Because tumor cell motility is required for metastasis, the effect of LM332 on MDA-MB-231 migration was determined using siRNA. Knockdown of LM332-specific ß3 and γ2 chains reduced motility without affecting viability. Our observation that LM332 in breast carcinoma is associated with decreased survival provides evidence that LM332 may have a role in the aggressive phenotype of some breast cancers.