Tumor Genomics Unit

Milano, Italy

Tumor Genomics Unit

Milano, Italy

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Hu J.,University of Oxford | Boeri M.,Tumor Genomics Unit | Sozzi G.,Tumor Genomics Unit | Liu D.,University of Oxford | And 5 more authors.
EBioMedicine | Year: 2015

Background: Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival. Methods: Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10. Findings: A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours. Interpretation: The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts. © 2015 The Authors.


PubMed | Spanish National Cancer Research Center, Vall dHebron Institute Oncology, University of Valencia, Hospital Universitari Of Bellvitge and 11 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

We aimed to maximize the performance of detecting genetic alterations in lung cancer (LC) using high-throughput sequencing for patient-derived xenografts (PDXs).We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of B2-microglobulin (B2M), a component of the HLA class-I complex.We identified alterations in genes involved in various functions, such as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to about 230 LCs. Five per cent of the LCs carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such as CALR, PDIA3 and TAP1, which are involved in the maturation of the HLA-I complex, are altered in LC. By gene expression microarrays, we observed that restitution of B2M in LC cells up-regulated targets of IFNalpha/IFNgamma. Furthermore, one third of the LCs lacked the HLA-I complex, which was associated with lower cytotoxic CD8+ lymphocyte infiltration. The levels of B2M and HLA-I proteins correlated with those of PD-L1. Finally, a deficiency in HLA-I complex and CD8+ infiltration tended to correlate with reduced survival of LC patients treated with anti-PD1-/anti-PD-L1.Here, we report recurrent inactivation of B2M in LC. These observations, coupled with the mutations found at CALR, PDIA3 and TAP1, and the down-regulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to LC development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies.


PubMed | University of Oxford, Fondazione IRCCS Instituto Nazionale dei Tumori, Medical Statistics and Bioinformatics Unit and Tumor Genomics Unit
Type: Journal Article | Journal: EBioMedicine | Year: 2015

Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival.Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10.A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.The distinct pattern of indolent and aggressive tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.


Castagnoli L.,Instituto Nazionale Dei Tumori | Iezzi M.,University of Chieti Pescara | Ghedini G.C.,Instituto Nazionale Dei Tumori | Ciravolo V.,Instituto Nazionale Dei Tumori | And 14 more authors.
Cancer Research | Year: 2014

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment. © 2014 American Association for Cancer Research.


PubMed | University of Padua, University of Verona, Instituto Oncologico Veneto IOV, Instituto Oncologico Veneto IRCCS and 6 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2017

LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC).We retrospectively analyzed LKB1 expression by immunohistochemistry in 98 samples out of 125 aNSCLC patients, including 59 patients treated with chemotherapy (CT) and 39 treated with CT plus bevacizumab. IHC intensity was re-coded in two classes (negative/weak versus moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models.In the whole study population (125), median OS and PFS were 11.7 (95%IC: 9.1-15.3) and 6.7 (95%IC: 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to treatment. Patients with negative/weak LKB1 status had not a statistically significant benefit from bevacizumab added to CT (HR for patients treated with bevacizumab: 0.89, 95% CI: 0.51-1.56, p=0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared to those not receiving bevacizumab (HR: 0.26, 95% CI: 0.10-0.64); p=0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.Our data hint at a possible predictive impact of LKB1 expression in aNSCLC patients treated with CT plus Bevacizumab.


PubMed | Fondazione IRCCS Instituto Nazionale Tumori, Fondazione IRCCS Instituto Nazionale dei Tumori and Tumor Genomics Unit
Type: | Journal: Cancer research | Year: 2016

Clinical efficacy of PD-1/PD-L1 targeting relies upon the reactivation of tumor-specific but functionally impaired PD-1+ T cells present before therapy. Thus, analyzing early stage primary tumors may reveal the presence of T cells that are not yet functionally impaired. In this study, we report that activated (HLA-DR+) T cells with an effector memory (TEM) profile are enriched in such lesions. Tumor-infiltrating lymphocytes (TIL) coexpressed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3 and TIGIT, but also displayed a recently activated, non-exhausted phenotype. We also identified a subset of CD8+PD-1+FOXP3+ T lymphocytes at the earliest phase of functional differentiation after priming, termed early effector cells (EEC), which also exhibited an activated non-exhausted phenotype, but was less differentiated and associated with coexpression of multiple inhibitory receptors. In response to autologous tumor, EEC upregulated CD107a, produced IL-2 and IFN-gamma and were competent for differentiation. The identification of EECs marked by inhibitory receptor expression at tumor sites will enable investigations of early stages of adaptive anti-tumor immunity, as well as support the rationale for administering immunotherapy in early stage NSCLC.

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