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Metadherin expression and lung relapse in patients with colorectal carcinoma

Publication . Casimiro, Sandra; Fernandes, Afonso; Oliveira, Antonio; Franco, Marco; Pires, Ricardo; Peres, Mafalda; Matias, Margarida; Tato-Costa, Joana; Carvalho Guerra, Nuno; Ramos, Madalena; Cruz, Jorge; Costa, Luis

Colorectal cancer (CRC) is the third most common malignant disease in men and the second in women worldwide. CRC relapse occurs mostly in liver and lungs, decreasing the 5-year survival to 6 %. Metadherin (MTDH) is overexpressed in several types of cancer, has been implicated in proliferation, invasion, metastasis, angiogenesis, and chemoresistance, and is a factor of poor prognosis in CRC. In this work we addressed the prognostic significance of MTDH expression in CRC progression to the lungs. We found that MTDH gene was more frequently amplified (copy number >1.8) in patients with CRC and relapse to the lung, when compared to patients without lung metastases (17.4 vs 100 %; p < 0.001). We observed a correlation between MTDH gene copy number and MTDH expression by IHC (p = 0.0001). Next we also analyzed MTDH expression by IHC in samples from 85 patients diagnosed with CRC, stage II or III, M0, with at least 3 years of follow-up. Kaplan-Meier survival analysis showed that lung relapse-free survival (HR 5.29, 95 % CI 1.90-14.77, p = 0.0004), liver relapse-free survival (HR 8.59, 95 % CI 0.99-74.18, p = 0.003), relapse-free survival (HR 4.85, 95 % CI 1.88-12.45, p = 0.0003) and overall survival (HR 3.75, 95 % CI 1.15-12.18, p = 0.018) were significantly lower in the group with high MTDH expression. Multivariate analysis showed that high MTDH expression was an independent factor for all outcomes. This study demonstrates that high MTDH expression is a biomarker of relapse in CRC, including lung-specific relapse. Determination of MTDH expression in primary CRC may be useful in the earlier detection of lung metastases in patients with high expression and increased risk.

2014Journal article

Restricted access

HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome

Publication . Golkaram, Mahdi; Salmans, Michael L.; Kaplan, Shannon; Vijayaraghavan, Raakhee; Martins, Marta; Khan, Nafeesa; Garbutt, Cassandra; Wise, Aaron; Yao, Joyee; Casimiro, Sandra; Marques, Catarina; Macedo, Daniela; Costa, Ana Lúcia; Alvim, Cecilia; Mansinho, André; Filipe, Pedro; Marques da Costa, Pedro; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Aldeia, Fernando; Malaquias, João; Godsey, Jim; So, Alex; Pawlowski, Traci; Costa, Luis; Zhang, Shile; Liu, Li

Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

2021Journal article

Open access

Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development

Publication . Sobral, Daniel; Martins, Marta; Kaplan, Shannon; Golkaram, Mahdi; Salmans, Michael; Khan, Nafeesa; Vijayaraghavan, Raakhee; Casimiro, Sandra; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Pinto, Rui; Marques, Catarina; Costa, Ana Lúcia; Zhang, Shile; Pawlowski, Traci; Godsey, Jim; Mansinho, André; Macedo, Daniela; Lobo-Martins, Soraia; Filipe, Pedro; Esteves, Rui; Coutinho, Joao; Costa, Paulo M.; Ramires, Afonso; Aldeia, Fernando; Quintela, António; So, Alex; Liu, Li; Grosso, Ana Rita; Costa, Luis

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.

2022Journal article

Open access