| 1. |
- Perez-Gracia, Jose Luis, et al.
(author)
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Strategies to design clinical studies to identify predictive biomarkers in cancer research
- 2017
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In: Cancer Treatment Reviews. - : Elsevier BV. - 0305-7372. ; 53, s. 79-97
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Research review (peer-reviewed)abstract
- The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework—the DESIGN guidelines—to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.
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| 2. |
- Ajona, Daniel, et al.
(author)
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Complement C4d-specific antibodies for the diagnosis of lung cancer
- 2018
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:5, s. 6346-6355
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Journal article (peer-reviewed)abstract
- Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for the diagnosis of lung cancer was 0.82 (95%CI = 0.72-0.92) in plasma samples, and 0.80 (95%CI = 0.69 to 0.90) in bronchoalveolar lavage fluids. In a set of plasma samples from the MILD CT-screening trial, the assay was unable to discriminate between asymptomatic high-risk individuals with or without early stage lung cancer. On the contrary, in two independent cohorts of individuals with indeterminate pulmonary nodules, plasma samples from patients with lung cancer nodules presented higher levels of C4d than those from patients with benign nodules. Using a target population of patients with 8 to 30 mm nodules, the test identified likely benign lung nodules with 84% negative predictive value and 54% positive predictive value, at 89% specificity and 44% sensitivity. In conclusion, the specific determination of C4d may serve as an adjunct to current clinical practice in the diagnosis of indeterminate pulmonary nodules.
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| 3. |
- Athie, Alejandro, et al.
(author)
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Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion
- 2020
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In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 219:9
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Journal article (peer-reviewed)abstract
- Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors. However, most of the altered regions are devoid of known cancer drivers. Here, we identify lncRNAs frequently lost or amplified in cancer. Among them, we found amplified lncRNA associated with lung cancer-1 (ALAL-1) as frequently amplified in lung adenocarcinomas. ALAL-1 is also overexpressed in additional tumor types, such as lung squamous carcinoma. The RNA product of ALAL-1 is able to promote the proliferation and tumorigenicity of lung cancer cells. ALAL-1 is a TNFα- and NF-κB-induced cytoplasmic lncRNA that specifically interacts with SART3, regulating the subcellular localization of the protein deubiquitinase USP4 and, in turn, its function in the cell. Interestingly, ALAL-1 expression inversely correlates with the immune infiltration of lung squamous tumors, while tumors with ALAL-1 amplification show lower infiltration of several types of immune cells. We have thus unveiled a pro-oncogenic lncRNA that mediates cancer immune evasion, pointing to a new target for immune potentiation.
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| 4. |
- Stacey, Simon N, et al.
(author)
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Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
- 2010
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In: PLoS genetics. - : Public Library of Science. - 1553-7404. ; 6:7, s. e1001029-
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Journal article (peer-reviewed)abstract
- We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.
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