Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles
PublisherBioMed Central Ltd.
MetadataShow full item record
AbstractRight-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors. Copyright 2018 The Author(s).
Left-sided colon cancer
Right-sided colon cancer
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85058907228&doi=10.1186%2fs12943-018-0923-9&partnerID=40&md5=bcfb1ef2085fecf4f73be21487bb7cfa; http://hdl.handle.net/10713/9706
Showing items related by title, author, creator and subject.
Managing the cancer–work interface: the effect of cancer survivorship on unemploymentTracy, J.K.; Falk, D.; Thompson, R.J. (Dove Medical Press Ltd, 2018)Objective: This study assessed differences in employment outcomes among cancer survivors using data from a nationally representative sample. Methods: The 2011 Medical Expenditure Panel Survey (MEPS) data and the 2011 MEPS Experiences with Cancer Survivorship Supplement representing 3,360,465 people in the US population were analyzed to evaluate factors associated with unemployment among cancer survivors during the 5 years following diagnosis and treatment. The sample included adults 1) diagnosed with cancer within 5 years prior to survey completion and 2) engaged in paid employment since diagnosis. Individuals diagnosed with nonmelanoma skin cancer (n=33) were excluded from analyses. Results: Data of 221 cancer survivors were used to identify factors associated with employment status at the time respondents were employed (n=155) vs unemployed (n=66). Results of bivariate analyses indicated that unemployed survivors were older, more likely to be women, more likely to be uninsured at the time of cancer diagnosis, and to report lower incomes than cancer survivors who continue to be employed. Unemployed survivors were more likely than employed survivors to have had anxiety about being forced to retire or quit early when they were employed because of cancer and to report cancer-related interference with physical and mental aspects of their job tasks; unemployed survivors also took less paid time off and were less likely to change to a flexible job schedule when they were employed. In multiple logistic regression analyses, worry about being forced to retire (protective), worry that cancer recurrence will interfere with home or work responsibilities (risk), and change to a flexible work schedule (risk) following cancer diagnosis were associated with unemployment after controlling for demographic differences between employed and unemployed cancer survivors. Conclusion: Findings of this study highlight the extent to which the challenges of managing the cancer-work interface create challenges to employment among cancer survivors and may lead to long-term unemployment among cancer survivors. Future studies should evaluate the strategies that the survivors could use to manage the cancer-work interface during cancer treatment to attain medical, psychological, social, and employment outcomes. Copyright 2018 Tracy et al.
The DNA synthesome: A model for studying breast cancer cell DNA replication and the mechanisms of action of anti-breast cancer agentsColl, Jennifer Marie; Malkas, Linda H. (1998)We have isolated a multiprotein complex for DNA synthesis, designated the DNA synthesome, from human breast cancer (MDA MB-468) cells, biopsied human breast tumor tissue and xenografts from nude mice injected with the human breast cancer cell line MCF-7. The breast cell DNA synthesome was shown to fully support the in vitro replication of simian virus 40 (SV40) origin-containing DNA in the presence of the viral large T-antigen. Moreover, our results obtained from a forward mutagenesis assay indicate that the DNA synthesome isolated from malignant breast cells possesses a lower fidelity for DNA replication in vitro than the complex from a nonmalignant breast cell line. The proteins and enzymes found to copurify with the breast cell DNA synthesome include: DNA polymerases alpha, delta, and epsilon, DNA primase, proliferating cell nuclear antigen (PCNA), replication factor C (RF-C), replication protein A (RP-A), DNA ligase, DNA topoisomerases I and II and poly(ADP-ribose) polymerase. To begin to determine the organization of these DNA synthetic proteins within the breast cell DNA synthesome, we performed co-immunoprecipitation experiments with antibodies directed against DNA polymerases alpha, delta and PCNA. We found that DNA polymerases alpha, delta, DNA primase, RF-C and PCNA tightly associate with each other in the complex, whereas DNA polymerase epsilon, PARP and several other components interact with the synthesome via an interaction with only PCNA or DNA polymerase alpha. Furthermore, we employed the breast cell DNA synthesome as a model to study the mechanisms of action of two anti-breast cancer agents that target the DNA synthetic process, irinotecan (CPT-11/SN-38) and etoposide (VP-16). We obtained novel data suggesting that both SN-38 and VP-16 stabilized cleavable complexes represent blocks to replication fork progression, as each agent caused an accumulation of short DNA products during synthesome mediated in vitro replication. Overall, our results indicate that breast cancer cells utilize an asymmetric multiprotein complex to mediate DNA synthesis and that utilization of the DNA synthesome as a drug model may provide important new insights into the mechanisms of action of SN-38 and VP-16.
Gastric microbiota features associated with cancer risk factors and clinical outcomes: A pilot study in gastric cardia cancer patients from Shanxi, ChinaYu, G.; Hu, N.; Wang, L. (Wiley-Liss Inc., 2017)Little is known about the link between gastric microbiota and the epidemiology of gastric cancer. In order to determine the epidemiologic and clinical relevance of gastric microbiota, we used 16 S ribosomal RNA gene sequencing analysis to characterize the composition and structure of the gastric microbial community of 80 paired samples (non-malignant and matched tumor tissues) from gastric cardia adenocarcinoma (GCA) patients in Shanxi, China. We also used PICRUSt to predict microbial functional profiles. Compared to patients without family history of upper gastrointestinal (UGI) cancer in the non-malignant gastric tissue microbiota, patients with family history of UGI cancer had higher Helicobacter pylori (Hp) relative abundance (median: 0.83 vs. 0.38, p = 0.01) and lower alpha diversity (median observed species: 51 vs. 85, p = 0.01). Patients with higher (vs. lower) tumor grade had higher Hp relative abundance (0.73 vs. 0.18, p = 0.03), lower alpha diversity (observed species, 66 vs. 89, p = 0.01), altered beta diversity (weighted UniFrac, p = 0.002) and significant alterations in relative abundance of five KEGG functional modules in non-malignant gastric tissue microbiota. Patients without metastases had higher relative abundance of Lactobacillales than patients with metastases (0.05 vs. 0.01, p = 0.04) in non-malignant gastric tissue microbiota. These associations were observed in non-malignant tissues but not in tumor tissues. In conclusion, this study showed a link of gastric microbiota to a major gastric cancer risk factor and clinical features in GCA patients from Shanxi, China. Studies with both healthy controls and gastric cardia and noncardia cancer cases across different populations are needed to further examine the association between gastric cancer and the microbiota. Copyright 2017 UICC