Publications by authors named "Julián Sanz"

20 Publications

  • Page 1 of 1

Management of Localized Muscle-Invasive Bladder Cancer from a Multidisciplinary Perspective: Current Position of the Spanish Oncology Genitourinary (SOGUG) Working Group.

Curr Oncol 2021 12 3;28(6):5084-5100. Epub 2021 Dec 3.

Medical Oncology Service, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain.

This review presents challenges and recommendations on different aspects related to the management of patients with localized muscle-invasive bladder cancer (MIBC), which were discussed by a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group within the framework of the Genitourinary Alliance project (12GU). It is necessary to clearly define which patients are candidates for radical cystectomy and which are candidates for undergoing bladder-sparing procedures. In older patients, it is necessary to include a geriatric assessment and evaluation of comorbidities. The pathological report should include a classification of the histopathological variant of MIBC, particularly the identification of subtypes with prognostic, molecular and therapeutic implications. Improvement of clinical staging, better definition of prognostic groups based on molecular subtypes, and identification of biomarkers potentially associated with maximum benefit from neoadjuvant chemotherapy are areas for further research. A current challenge in the management of MIBC is improving the selection of patients likely to be candidates for immunotherapy with checkpoint inhibitors in the neoadjuvant setting. Optimization of FDG-PET/CT reliability in staging of MIBC and the selection of patients is necessary, as well as the design of prospective studies aimed to compare the value of different imaging techniques in parallel.
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http://dx.doi.org/10.3390/curroncol28060428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700266PMC
December 2021

Ovarian yolk sac tumor.

Int J Gynecol Cancer 2021 05;31(5):797-798

Servicio de Anatomía Patológica, Clínica Universidad de Navarra, Madrid, Spain.

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http://dx.doi.org/10.1136/ijgc-2021-002538DOI Listing
May 2021

Molecular biomarkers in early stage lung cancer.

Transl Lung Cancer Res 2021 Feb;10(2):1165-1185

Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

Low dose computed tomography (LDCT) screening, together with the recent advances in targeted and immunotherapies, have shown to improve non-small cell lung cancer (NSCLC) survival. Furthermore, screening has increased the number of early stage-detected tumors, allowing for surgical resection and multimodality treatments when needed. The need for improved sensitivity and specificity of NSCLC screening has led to increased interest in combining clinical and radiological data with molecular data. The development of biomarkers is poised to refine inclusion criteria for LDCT screening programs. Biomarkers may also be useful to better characterize the risk of indeterminate nodules found in the course of screening or to refine prognosis and help in the management of screening detected tumors. The clinical implications of these biomarkers are still being investigated and whether or not biomarkers will be included in further decision-making algorithms in the context of screening and early lung cancer management still needs to be determined. However, it seems clear that there is much room for improvement even in early stage lung cancer disease-free survival (DFS) rates; thus, biomarkers may be the key to refine risk-stratification and treatment of these patients. Clinicians' capacity to register, integrate, and analyze all the available data in both high risk individuals and early stage NSCLC patients will lead to a better understanding of the disease's mechanisms, and will have a direct impact in diagnosis, treatment, and follow up of these patients. In this review, we aim to summarize all the available data regarding the role of biomarkers in LDCT screening and early stage NSCLC from a multidisciplinary perspective. We have highlighted clinical implications, the need to combine risk stratification, clinical data, radiomics, molecular information and artificial intelligence in order to improve clinical decision-making, especially regarding early diagnostics and adjuvant therapy. We also discuss current and future perspectives for biomarker implementation in routine clinical practice.
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http://dx.doi.org/10.21037/tlcr-20-750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947407PMC
February 2021

[Updated guidelines for predictive biomarker testing in advanced non-small-cell lung cancer: A National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology].

Rev Esp Patol 2020 Jul - Sep;53(3):167-181. Epub 2020 Jun 16.

Departamento de Oncología Médica, Hospital Universitario Ramón y Cajal, Universidad Alcalá, IRYCIS, CIBERONC, Madrid, España.

In 2011, the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) initiated a joint project to establish guidelines for biomarker testing in patients with advanced non-small-cell lung cancer based on the information available at the time. As this field is constantly evolving, these guidelines were updated in 2012 and 2015 and now in 2019. Current evidence suggests it should be mandatory to test all patients with this kind of advanced lung cancer for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). However, the coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remain a challenge.
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http://dx.doi.org/10.1016/j.patol.2019.11.004DOI Listing
September 2021

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

J Thorac Oncol 2019 12 23;14(12):2120-2132. Epub 2019 Jul 23.

Alvaro Cunqueiro Hospital, Vigo, Spain.

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data.

Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific).

Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively).

Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.
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http://dx.doi.org/10.1016/j.jtho.2019.07.005DOI Listing
December 2019

Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing.

Sci Rep 2019 07 8;9(1):9814. Epub 2019 Jul 8.

Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, IdISSC, CIBERONC, Madrid, Spain.

Attenuated adenomatous polyposis (AAP) is a heterogeneous syndrome in terms of clinical manifestations, heritability and etiology of the disease. Genetic heterogeneity and low penetrance alleles are probably the best explanation for this variability. Certainly, it is known that APC and MUTYH are high penetrance predisposition genes for adenomatous polyposis, but they only account for 5-10% of AAP. Other new predisposition genes, such as POLE, POLD1, NTHL1, AXIN2 or MSH3, have been recently described and have been associated with AAP, but their relative contribution is still not well defined. In order to evaluate the genetic predisposition to AAP in a hospital based population, germline DNAs from 158 AAP subjects were screened for genetic variants in the coding regions and intron-exon boundaries of seven associated genes through a next-generation sequencing (NGS) custom gene panel. Splicing, segregation studies, somatic mutational screening and RNA quantitative expression assays were conducted for selected variants. In four of the probands the adenoma susceptibility could be explained by actionable mutations in APC or MUTYH, and one other patient was a double carrier of two truncating variants in both POLE and NTHL1. Furthermore, 16 additional patients harbored uncertain significance variants in the remaining tested genes. This report gives information about the contribution of the newly described adenomatous polyposis predisposition genes in a Spanish attenuated polyposis cohort. Our results highly support the convenience of NGS multigene panels for attenuated polyposis genetic screening and reveals POLE frameshift variants as a plausible susceptibility mechanism for AAP.
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http://dx.doi.org/10.1038/s41598-019-46403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614360PMC
July 2019

c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial-Mesenchymal Transition and Regulates Cell Phenotypic Switch.

Stem Cells 2019 08 18;37(8):1108-1118. Epub 2019 Jun 18.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.

Adult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelial-mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives. Stem Cells 2019;37:1108-1118.
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http://dx.doi.org/10.1002/stem.3038DOI Listing
August 2019

[2018 Consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary].

Rev Esp Patol 2019 Jan - Mar;52(1):33-44. Epub 2018 Oct 10.

Servicio de Oncología Médica, Institut Català d'Oncologia ICO-Hospitalet/Hospital de Sant Joan Despí - Moisès Broggi, Sant Joan Despí, Barcelona, España.

Cancer of unknown primary is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, cancer of unknown primary can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological and molecular studies conducted to analyse and determine the origin of cancer of unknown primary. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.
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http://dx.doi.org/10.1016/j.patol.2018.08.002DOI Listing
May 2020

Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

Liver Int 2018 09 25;38(9):1664-1675. Epub 2018 May 25.

Faculty of Pharmacy, Department Biochemistry and Molecular Biology, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.

Background & Aims: Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion.

Methods: WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects.

Results: Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor.

Conclusions: We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases.
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http://dx.doi.org/10.1111/liv.13879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693351PMC
September 2018

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma.

Oncotarget 2017 May;8(18):30410-30421

Molecular Oncology Unit CIEMAT and Instituto Investigación Biomédica, Hospital Universitario 12 de Octubre, Madrid, Spain.

Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation.

Patients And Methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS.

Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found.

Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response.
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http://dx.doi.org/10.18632/oncotarget.16494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444752PMC
May 2017

Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging.

BMC Cancer 2017 03 22;17(1):210. Epub 2017 Mar 22.

Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.

Background: Accurate measurement of tumor burden in breast cancer disease is essential to improve the clinical management of patients. In this study, we evaluate whether the fluctuations in the fraction of PIK3CA mutant allele correlates with tumor response according to RECIST criteria and tumor markers quantification.

Methods: Eighty six plasma samples were analyzed by digital PCR using Rare Mutation Assays for E542K, E545K and H1047R. Mutant cfDNA and tumor markers CA15-3 and CEA were compared with radiographic imaging.

Results: The agreement between PIK3CA mutation status in FFPE samples and circulating tumor DNA (ctDNA) was moderate (K = 0.591; 95% IC = 0.371-0.811). Restricting the analysis to the metastatic patients, we found a good agreement between PIK3CA mutation status assessed in liquid and solid biopsy (K = 0.798 95%; IC = 0.586-1). ctDNA showed serial changes with fluctuations correlating with tumor markers 15.3 and CEA in 7 out of 8 cases with Pearson correlation coefficients ranging from 0.99 to 0.46 and from 0.99 to 0.38 respectively. Similarly, fluctuations in the fraction of PIK3CA mutant allele always correlated with changes in lesion size seen on images, although in two cases it did not correlate with treatment responses as defined by RECIST criteria.

Conclusion: oncogenic mutation quantification in plasma samples can be useful to monitor treatment outcome. However, it might be limited by tumor heterogeneity in advanced disease and it should be evaluated together with radiographic imaging.
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http://dx.doi.org/10.1186/s12885-017-3185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362993PMC
March 2017

Identification of E545k mutation in plasma from a PIK3CA wild-type metastatic breast cancer patient by array-based digital polymerase chain reaction: Circulating-free DNA a powerful tool for biomarker testing in advance disease.

Transl Res 2015 Dec 27;166(6):783-7. Epub 2015 Apr 27.

Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.

PIK3CA gene is frequently mutated in patients with breast cancer and it has been the focus of intense research. Inhibitors of PI3K pathway are being evaluated in ongoing clinical trials but the impact of PIKC3A mutation status on tumor response is yet uncertain. In the metastatic setting, several studies are evaluating the predictive value of PIK3CA mutations. However, results could be biased by biopsy localization. Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood and can potentially overcome such situation. As a proof of the concept, we present the case of a metastatic patient with a PIK3CA wild-type primary tumor in which the PIK3CA E545K mutation was identified in both the circulating-free DNA obtained from a peripheral blood sample and in the formalin-fixed, paraffin-embedded liver metastasis.
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http://dx.doi.org/10.1016/j.trsl.2015.04.010DOI Listing
December 2015

Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry.

PLoS One 2014 23;9(9):e107200. Epub 2014 Sep 23.

Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico "Clara Campal", Hospital Universitario Madrid Sanchinarro, Universidad San Pablo-CEU, Madrid, Spain.

Background: Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples.

Methods: Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview's automated scanning system.

Results: All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively.

Conclusions: The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107200PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172507PMC
June 2015

Relationship of immunohistochemical biomarker expression and lymph node involvement in patients undergoing surgical treatment of NSCLC with long-term follow-up.

Tumour Biol 2014 May 19;35(5):4551-9. Epub 2014 Jan 19.

Thoracic Surgery Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), C/Martin Lagos s/n, 28040, Madrid, Spain.

We try to identify the relationship between immunohistochemical marker expression and lymph node involvement in a cohort of 282 patients followed for 5 years after curative resection for NSCLC. In 189 patients (67%), lymph nodes were unaffected while 93 patients (33%) showed nodal involvement. The expression of 15 molecular markers was determined from each patient by tissue-array immunohistochemistry. Univariate analysis indicated significantly higher expression of E-cadherin, γ-catenin, p27, and p53 in patients with lymph node involvement. In those with unaffected nodes, p16 and Rb were expressed. E-cadherin expression was related to a 50% mortality reduction in patients with node involvement (hazard ratio (HR) 0.5; p = 0.017). c-erbB-2 expression was correlated with a 3.4-fold increase in mortality compared to patients without expression of this marker in subjects without node involvement (HR 3.41; p = 0.017). Multivariate analysis identified c-erbB-2 (HR 2.22; p = 0.089) and p27 (HR 1.44; p = 0.019) as prognostics of mortality while Rb (HR 0.74) indicated a good prognosis. The expression of proteins encoded by oncogenes and tumor suppressor genes was different according to lymph node involvement. The increased mortality related to c-erbB-2 expression in patients with unaffected lymph nodes would suggests a need for adjuvant treatment.
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http://dx.doi.org/10.1007/s13277-013-1599-9DOI Listing
May 2014

Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer.

Fam Cancer 2014 Mar;13(1):109-19

Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, IdISSC, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain,

Mismatch repair proficient hereditary non-polyposis colorectal cancer (MSS-HNPCC) encloses a heterogeneous group of families consisting of different unknown genetic syndromes and/or aggregations cases. The lack of information about the hereditability of cancer risk in these families makes it difficult to carry out an individualized Genetic Counseling. Therefore, deep description of such families becomes important for a better classification and search for underlying susceptibility causes. The aim of this study is to describe and compare the clinical, morphological features, tumor KRAS status and overall survival in MSS-HNPCC, Lynch and sporadic colorectal cancer. A total of 37 MSS-HNPCC families, 50 Lynch families and 612 sporadic CRC were included. Clinical and morphological data were evaluated by reviewing medical and pathology reports of 55, 69 and 102 tumors respectively. KRAS/BRAF status were detected by allele specific real-time PCR. Standardized incidence ratios (SIR) were calculated among 602 MSS-HNPCC relatives and 668 Lynch relatives. Main features distinguishing MSS-HNPCC were diagnosis age (55.1 ± 12.6), preferential distal location (76%), polyp detection (45%) and familial colorectal cancer incidence (SIR = 6.6). In addition, we found increased incidences rates for kidney, stomach and uterus tumors. KRAS mutation rates were similar in the study populations (48.8 ± 5.8) but higher than those described before by Sanger sequencing. MSS-HNPCC overall survival was similar to Lynch in B Dukes' stage tumors and between Lynch and sporadic in C stage tumors. Anatomical and morphological data of MSS-HNPCC are consistent with other described populations. Our studies disclose an increased HNPCC-extracolonic tumors incidence and improved overall survival in MSS-HNPCC families.
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http://dx.doi.org/10.1007/s10689-013-9683-2DOI Listing
March 2014

Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

PLoS One 2013 11;8(9):e72195. Epub 2013 Sep 11.

Molecular Oncology Laboratory, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.

Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770653PMC
June 2014

Guidelines for biomarker testing in advanced non-small-cell lung cancer. A national consensus of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP).

Clin Transl Oncol 2012 May;14(5):338-49

Medical Oncology Service, Universitary Hospital Ramón y Cajal, Madrid, Spain.

Patients with advanced non-small-cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations can now have specific treatment based on the result of biomarker analysis and patients with rearrangements of the anaplastic lymphoma kinase (ALK) gene will probably soon be able to. This will give them better quality of life and progression-free survival than conventional chemotherapy. This consensus statement was conceived as a joint initiative of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP), and makes diagnostic and treatment recommendations for advanced NSCLC patients based on the scientific evidence on biomarker use. It therefore provides an opportunity to improve healthcare efficiency and resource use, which will undoubtedly benefit these patients. Although this field is in continuous evolution, at present, with the available data, this panel of experts recommends that all patients with advanced NSCLC of non-squamous cell subtype, or non-smokers regardless of the histological subtype, should be tested for EGFR gene mutations within a maximum of 7 days from the pathological diagnosis. Involved laboratories must participate in external quality control programmes. In contrast, ALK gene rearrangements should only be tested in the context of a clinical trial, although the promising data obtained will certainly justify in the near future its routine testing in patients with no EGFR mutations. Lastly, routine testing for other molecular abnormalities is not considered necessary in the current clinical practice.
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http://dx.doi.org/10.1007/s12094-012-0806-2DOI Listing
May 2012

Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab.

Clin Colorectal Cancer 2012 Dec 25;11(4):291-6. Epub 2012 Apr 25.

Department of Clinical Oncology, Hospital Clínico San Carlos (HCSC), Madrid, Spain.

Background: Patients with metastatic colorectal cancer (mCRC) with activating mutations at codon 12 or 13 of the KRAS gene are currently excluded from treatment with monoclonal antibodies against the epidermal growth factor receptor (EGFR), for example, cetuximab. Occasionally, some of these patients benefit from treatment with cetuximab, especially patients with a mutation at codon 13. We conducted an analysis to study the influence of the KRAS p.G13D mutation in patients with mCRC who were treated with cetuximab.

Materials And Methods: We analyzed the KRAS mutation status of 110 patients who were treated with cetuximab between September 2003 and October 2008 at Hospital Clínico, San Carlos. We compared progression-free survival, overall survival, and response rate according to KRAS mutation status.

Results: Patients with mutations at codon 13 compared with those with other KRAS mutations showed no statistically significant differences in progression-free survival (4.96 months [95% CI, 3.04-6.89 months] vs. 3.10 months [95% CI, 1.58-4.61 months]; hazard ratio [HR] 0.88 [95% CI, 44-1.75]; P = .72) and overall survival (8.2 months [95% CI, 4.2-12.1 months] vs. 14.6 months [95% CI, 8.0-21.2 months]; HR 0.50 [95% CI, 0.23-1.09]; P = .084). Patients with KRAS wild-type tumors have a longer progression-free survival (7.30 months [95% CI, 4.48-10.12 months]; HR 0.46 [95% CI, 0.23-0.91]; P = .025) and overall survival (19.0 months [95% CI, 10.2-27.8 months]; HR 0.32 [95% CI, 0.15-0.69]; P = .004) than patients with p.G13D-mutated tumors. Differences in the response rate were not observed between groups.

Conclusion: Patients with mCRC and mutation at codon 13 of the KRAS gene do not appear to benefit from treatment with cetuximab. These results support the current clinical practice.
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http://dx.doi.org/10.1016/j.clcc.2012.02.003DOI Listing
December 2012

Analysis of the oxidative damage repair genes NUDT1, OGG1, and MUTYH in patients from mismatch repair proficient HNPCC families (MSS-HNPCC).

Clin Cancer Res 2011 Apr 25;17(7):1701-12. Epub 2011 Feb 25.

Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, Madrid, Spain.

Purpose: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1.

Experimental Design: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families.

Results: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1.

Conclusions: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2491DOI Listing
April 2011

Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer.

Oncol Rep 2004 Sep;12(3):621-9

Molecular Oncology Laboratory, Hospital Clínico San Carlos, Martin Lagos s/n, 28040 Madrid, Spain.

Hereditary non-polyposis colorectal cancer (HNPCC) represents 1-3% of all colorectal cancers. HNPCC is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2 and MSH6. The MMR defect results in an increased cancer risk, with the greatest lifetime risk for colorectal cancer and other cancers associated to HNPCC. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. The aim of this study was to determine the sensitivity of IHC for MLH1, MSH2 and MSH6, and MSI analysis in tumors from known MMR gene mutation carriers. Fifty-eight paired normal and tumor samples from HNPCC families enrolled in our high-risk colorectal cancer registry were studied for the presence of germline mutations in MLH1, MSH2 and MSH6 by DGGE and direct sequencing. MSI analysis and immunostaining for MLH1, MSH2 and MSH6 were evaluated. Of the 28 patients with a real pathogenic mutation, loss of immunohistochemical expression for at least 1 of these MMR proteins was found, and all except 1 have MSI-H. Sensitivity by MSI analysis was 96%. IHC analysis had a sensitivity of 100% in detecting MMR deficiency in carriers of a pathogenic MMR mutation, and can be used to predict which gene is expected to harbor the mutation for MLH1, MSH2 and MSH6. This study suggests that both analyses are useful for selecting high-risk patients because most MLH1, MSH2 and MSH6 gene carriers will be detected by this 2-step approach. This practical method should have immediate application in the clinical work of patients with inherited colorectal cancer syndromes.
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September 2004
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