Oncotarget | https://doi.org/10.18632/oncotarget.12140 José María Sayagués, Luís Antonio Corchete, María Laura Gutiérrez, Maria Eugenia Sarasquete, María del Mar Abad, Oscar Bengoechea, Encarna Fermiñán, María... Genomic characterization of liver metastases from colorectal cancer patients

Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer; most patients die during the first 6 months after diagnosis. With a 5% 5-year survival rate, is the fourth leading cause of cancer death in developed countries. In this regard, several clinical, histopathologic and biological characteristics of the disease favoring long-term survival after pancreaticoduodenectomy have been reported to be significant prognostic factors. Despite the availability of this information, there is no consensus about the different prognostic factors reported in the literature, probably due to variations in patient selection, methods, and sample size studied. The aim of this study was to identify the clinical and pathologic features associated to prognosis of the disease after pancreaticoduodenectomy. Materials and Methods: The clinical and pathologic data from 78 patients who underwent a potentially curative resection for PDAC at our institution between 2003 and 2014 were analyzed retrospectively. Results: Overall, high-grade PDAC cases showed larger tumor size (P=0.009) and a higher frequency of deaths in association with a nonsignificantly shortened patient overall survival (median of 12.5 vs. 21.7 mo; P=0.065) as compared with low-grade PDAC patients. High histologic grade (P=0.013), preoperative drainage on the main bile duct (P=0.014) and absence of adjuvant therapy (P=0.035) were associated with a significantly poorer outcome. Overall survival multivariate analysis showed histologic grade (P=0.019) and bile duct preoperative drainage (P=0.016) as the sole independent variables predicting an adverse outcome. Conclusions: Our results indicate that histologic tumor grade and preoperative biliary drainage are the only significant independent prognostic factors in PDAC patients after pancreatectomy.

An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

For years, the genetics of metastatic colorectal cancer (CRC) have been studied using a variety of techniques. However, most of the approaches employed so far have a relatively limited resolution which hampers detailed characterization of the common recurrent chromosomal breakpoints as well as the identification of small regions carrying genetic changes and the genes involved in them. Here we applied 500K SNP arrays to map the most common chromosomal lesions present at diagnosis in a series of 23 primary tumours from sporadic CRC patients who had developed liver metastasis. Overall our results confirm that the genetic profile of metastatic CRC is defined by imbalanced gains of chromosomes 7, 8q, 11q, 13q, 20q and X together with losses of the 1p, 8p, 17p and 18q chromosome regions. In addition, SNP-array studies allowed the identification of small (1.5 Mb) altered DNA sequences, many of which contain cancer genes known to be involved in CRC and the metastatic process. Detailed characterization of the breakpoint regions for the altered chromosomes showed four recurrent breakpoints at chromosomes 1p12, 8p12, 17p11.2 and 20p12.1; interestingly, the most frequently observed recurrent chromosomal breakpoint was localized at 17p11.2 and systematically targeted the FAM27L gene, whose role in CRC deserves further investigations. In summary, in the present study we provide a detailed map of the genetic abnormalities of primary tumours from metastatic CRC patients, which confirm and extend on previous observations as regards the identification of genes potentially involved in development of CRC and the metastatic process.

BACKGROUND: Metastatic dissemination is the most frequent cause of death in patients with sporadic colorectal cancer (sCRC). It is believed that the metastatic process is related at least in part to a specific background of genetic alterations accumulated in cells from primary tumors, and the ability to detect such alterations is critical for the identification of patients with sCRC who are at risk of developing metastases.METHODS: The authors used high‐resolution, 500‐K single nucleotide polymorphism arrays to identify copy number alteration profiles present at diagnosis in primary tumors from patients with metastatic (n = 23) versus nonmetastatic (n = 26) sCRC.RESULTS: The results revealed a characteristic pattern of copy number alterations in metastatic sCRC tumors that involved losses of 23 regions at chromosomes 1p, 17p, and 18q, together with gains of 35 regions at chromosomes 7 and 13q.CONCLUSIONS: In line with expectations, the copy number profile investigated involved multiple genes that were associated previously with sCRC (ie, SMAD2) and/or the metastatic process (ie, podocalyxin‐like [PODXL]), and it also was associated with a poorer outcome. Cancer 2014;120:1948–1959. © 2014 American Cancer Society.