Marcos González-Díaz

Instituto de Investigación Biomédica de A Coruña, La Corogne, Galicia, Spain

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Publications (13)259.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in Toll-like receptor and MYD88 genes (TLR/MYD88) have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics and outcome of patients with mutations in TLR/MYD88 in 587 CLL patients by either whole-exome or Sanger sequencing. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1 and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL cells overexpressed genes of the NFkB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% ≤50 years) than unmutated, with this being the most frequent mutation in this subgroup of patients. Mutated TLR/MYD88 CLL had higher frequency of mutated IGHV and low expression of CD38 or ZAP-70. Overall survival (OS) was better in TLR/MYD88 mutated than unmutated in the whole series (10-year OS: 100% vs. 62%; p=0.002), and in the subset of patients ≤50 years (100% vs. 70%; p=0.02). In addition, relative OS of TLR/MYD88 mutated patients was similar to age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.
    Blood 04/2014; · 9.06 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is considered a distinct type of B-cell lymphoma genetically characterized by the t(11;14) translocation and cyclin D1 overexpression. There is also a small subset of tumors negative for cyclin D1 expression that are morphologically and immunophenotypically indistinguishable from conventional MCL. Although in the last decades, the median overall survival of patients with MCL has improved significantly, it is still considered as one of the poorest prognoses diseases among B-cell lymphomas. Election of treatment for patients with MCL is complex due to the scarcity of solid evidence. Current available data shows that conventional chemotherapy does not yield satisfactory results as in other types of B-cell lymphomas. However, the role of other approaches such as autologous or allogenic stem cell transplantation, immunotherapy, the administration of consolidation or maintenance schedules, or the use of targeted therapies still lack clear indications. In view of this situation, the Spanish Group of Lymphomas/Autologous Bone Marrow Transplantation has conducted a series of reviews on different aspects of MCL, namely its diagnosis, prognosis, first-line and salvage treatment (both in young and elderly patients), new targeted therapies, and detection of minimal residual disease. On the basis of the available evidence, a series of recommendations have been issued with the intention of providing guidance to clinicians on the diagnosis, treatment, and monitoring of patients with MCL.
    Annals of Hematology 05/2013; · 2.87 Impact Factor
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    ABSTRACT: Follicular mucinosis (FM) is an uncommon reaction pattern in which the accumulation of mucin in the follicular epithelium is the main pathologic finding. FM may be idiopathic (primary follicular mucinosis [PFM]), in association with mycosis fungoides or cutaneous T-cell lymphoma, or in association with other neoplastic and inflammatory conditions. Herein we report a case of PFM with identical T-cell clone rearrangement at anatomically distinct sites, supporting the idea that some authors have proposed, that FM may represent a low-grade lymphoproliferative disease related to mycoses fungoides with favorable prognosis.
    Pediatric Dermatology 03/2013; · 1.04 Impact Factor
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    ABSTRACT: NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.Leukemia advance online publication, 8 January 2013; doi:10.1038/leu.2012.357.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2012; · 10.16 Impact Factor
  • J Labrador, N Puig, A Ortín, N C Gutierrez, M González-Díaz
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    ABSTRACT: All-trans retinoic acid (ATRA) induces complete remission in 64-100 % of patients with acute promyelocytic leukemia (APL), and is considered to be a safe agent. Pseudotumor cerebri is a neurological side effect of ATRA reported in pediatric patients, and which is characterized by raised cerebrospinal fluid pressure in the absence of any intracranial pathology or secondary causes of intracranial hypertension. Involvement of cranial nerves other than II and VI is very uncommon in idiopathic intracranial hypertension (IIH); peripheral facial nerve palsy is exceptional and has rarely been described in the context of treatment with ATRA. We describe the case of a 15-year-old female patient with APL who developed an IIH and involvement of cranial nerves (bilateral papilledema, left facial and right sixth nerves) after receiving induction therapy including ATRA. Viral infections and other causes of secondary cranial nerve lesions were excluded. Symptoms completely subsided with the temporary withdrawal of ATRA and did not recur after reintroducing the drug. To date, the patient has managed to receive the treatment as per protocol. In conclusion, we report an atypical presentation of IIH that merits consideration, especially with respect to young patients with APL receiving ATRA; our most important observation is that the drug could be safely reintroduced once the symptoms had resolved.
    International journal of hematology 07/2012; 96(3):383-5. · 1.17 Impact Factor
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    ABSTRACT: Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.
    Nature Genetics 12/2011; 44(1):47-52. · 35.21 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukaemia (CLL), the most frequent leuk-aemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution 1,2 . Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes 3,4 . The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene func-tion. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immu-noglobulins. The patterns of somatic mutation, supported by func-tional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our know-ledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the iden-tification of clinically relevant mutations in cancer. To gain insights into the molecular alterations that cause CLL, we performed whole-genome sequencing of four cases representative of different forms of the disease: two cases, CLL1 and CLL2, with no mutations in the immunoglobulin genes (IGHV-unmutated) and two cases, CLL3 and CLL4, with mutations in these genes (IGHV-mutated) (Supplementary Table 1 and Supplementary Information). We used a combination of whole-genome sequencing and exome sequencing, as well as long-insert paired-end libraries, to detect variants in chromo-somal structure (Supplementary Fig. 1 and Supplementary Tables 2–5). We obtained more than 99.7% concordance between whole-genome sequencing calls and genotyping data, indicating that the coverage and parameters used were sufficient to detect most of the sequence variants in these samples (Supplementary Information). We detected about 1,000 somatic mutations per tumour in non-repetitive regions (Fig. 1a, Supplementary Fig. 2 and Supplementary Table 6). These numbers of somatic mutations were lower than the numbers in mela-noma and lung carcinoma 5,6 , but in agreement with previous estimates of less than one mutation per megabase (Mb) for leukaemias 7 . The most common substitution was the transition G.A/C.T, usually occurring in a CpG context (Fig. 1b and Supplementary Fig. 2). We also detected marked differences in the mutation pattern between CLL samples and these differences were associated with tumour subtype (Fig. 1b). Thus, IGHV-mutated cases showed a higher proportion of A.C/T.G muta-tions than cases with unmutated IGHV (16 6 0.2% versus 6.2 6 0.1%). The base preceding the adenine in A to C transversions showed an over-representation of thymine, when compared to the prevalence expected from its representation in non-repetitive sequences in the wild-type genome (P , 0.001, Fig. 1c), and there were fewer A to C substitutions at GpA dinucleotides than would be expected by chance (P , 0.001). These differences between CLL subtypes might reflect the molecular mechanisms implicated in their respective development. The pattern and context of mutations are consistent with their being introduced by the error-prone polymerase g during somatic hypermutation in immunoglobulin genes 8 . This indicates that polymerase g could con-tribute to the high frequency of A . T to C . G transversions in cases with IGHV-mutated. It also extends the differences observed between these two CLL subtypes to the genomic level. We classified the somatic mutations into three different classes according to their potential functional effect (Supplementary Informa-tion). We also searched for small insertions and deletions (indels) in coding regions: we found and validated five somatic indels, which caused frameshifts in protein-coding regions (Supplementary Table 7).
    Nature 07/2011; 475(7354):101-105. · 38.60 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
    Nature 06/2011; 475(7354):101-5. · 38.60 Impact Factor
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    Annals of Hematology 02/2011; 90(2):227-9. · 2.87 Impact Factor
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    ABSTRACT: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
    Nature 04/2010; 464:993-8. · 38.60 Impact Factor
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    ABSTRACT: For years, the genetics of metastatic colorectal cancer (CRC) have been studied using a variety of techniques. However, most of the approaches employed so far have a relatively limited resolution which hampers detailed characterization of the common recurrent chromosomal breakpoints as well as the identification of small regions carrying genetic changes and the genes involved in them. Here we applied 500K SNP arrays to map the most common chromosomal lesions present at diagnosis in a series of 23 primary tumours from sporadic CRC patients who had developed liver metastasis. Overall our results confirm that the genetic profile of metastatic CRC is defined by imbalanced gains of chromosomes 7, 8q, 11q, 13q, 20q and X together with losses of the 1p, 8p, 17p and 18q chromosome regions. In addition, SNP-array studies allowed the identification of small (<1.3 Mb) and extensive/large (>1.5 Mb) altered DNA sequences, many of which contain cancer genes known to be involved in CRC and the metastatic process. Detailed characterization of the breakpoint regions for the altered chromosomes showed four recurrent breakpoints at chromosomes 1p12, 8p12, 17p11.2 and 20p12.1; interestingly, the most frequently observed recurrent chromosomal breakpoint was localized at 17p11.2 and systematically targeted the FAM27L gene, whose role in CRC deserves further investigations. In summary, in the present study we provide a detailed map of the genetic abnormalities of primary tumours from metastatic CRC patients, which confirm and extend on previous observations as regards the identification of genes potentially involved in development of CRC and the metastatic process.
    PLoS ONE 01/2010; 5(10):e13752. · 3.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
    Nature 01/2010; 464(7291):993-8. · 38.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
    Nature 464(7291):993-8. · 38.60 Impact Factor

Publication Stats

900 Citations
259.09 Total Impact Points

Institutions

  • 2013
    • Instituto de Investigación Biomédica de A Coruña
      La Corogne, Galicia, Spain
  • 2010–2013
    • Hospital Universitario de Salamanca
      • Servicio de Oncología Radioterápica
      Helmantica, Castille and León, Spain
  • 2012
    • Universidad de Salamanca
      Helmantica, Castille and León, Spain