An Optimizing Protocol Transformation for Constructor Finite Variant Theories in Maude-NPA

[EN] Maude-NPA is an analysis tool for cryptographic security protocols that takes into account the algebraic properties of the cryptosystem. Maude-NPA can reason about a wide range of cryptographic properties. However, some algebraic properties, and protocols using them, have been beyond Maude-NPA capabilities, either because the cryptographic properties cannot be expressed using its equational unification features or because the state space is unmanageable. In this paper, we provide a protocol transformation that can safely get rid of cryptographic properties under some conditions. The time and space difference between verifying the protocol with all the crypto properties and verifying the protocol with a minimal set of the crypto properties is remarkable. We also provide, for the first time, an encoding of the theory of bilinear pairing into Maude-NPA that goes beyond the encoding of bilinear pairing available in the Tamarin toolPartially supported by the EU (FEDER) and the Spanish MCIU under grant RTI2018-094403-B-C32, by the Spanish Generalitat Valenciana under grant PROMETEO/2019/098, and by the US Air Force Office of Scientific Research under award number FA9550-17-1-0286. Julia Sapiña has been supported by the Generalitat Valenciana APOSTD/2019/127 grantAparicio-Sánchez, D.; Escobar Román, S.; Gutiérrez Gil, R.; Sapiña-Sanchis, J. (2020). An Optimizing Protocol Transformation for Constructor Finite Variant Theories in Maude-NPA. Springer Nature. 230-250. https://doi.org/10.1007/978-3-030-59013-0_12S230250Maude-NPA manual v3.1. http://maude.cs.illinois.edu/w/index.php/Maude_Tools:_Maude-NPAThe Tamarin-Prover Manual, 4 June 2019. https://tamarin-prover.github.io/manual/tex/tamarin-manual.pdfAl-Riyami, S.S., Paterson, K.G.: Tripartite authenticated key agreement protocols from pairings. In: Paterson, K.G. (ed.) Cryptography and Coding 2003. LNCS, vol. 2898, pp. 332–359. Springer, Heidelberg (2003). https://doi.org/10.1007/978-3-540-40974-8_27Baader, F., Snyder, W.: Unification theory. In: Robinson, J.A., Voronkov, A. (eds.) Handbook of Automated Reasoning, vol. 1, pp. 447–533. Elsevier Science (2001)Baelde, D., Delaune, S., Gazeau, I., Kremer, S.: Symbolic verification of privacy-type properties for security protocols with XOR. In: 30th IEEE Computer Security Foundations Symposium, CSF 2017, pp. 234–248. IEEE Computer Society (2017)Blanchet, B.: Modeling and verifying security protocols with the applied pi calculus and ProVerif. Found. Trends Privacy Secur. 1(1–2), 1–135 (2016)Clavel, M., et al.: Maude manual (version 3.0). Technical report, SRI International, Computer Science Laboratory (2020). http://maude.cs.uiuc.eduComon-Lundh, H., Delaune, S.: The finite variant property: how to get rid of some algebraic properties. In: Giesl, J. (ed.) RTA 2005. LNCS, vol. 3467, pp. 294–307. Springer, Heidelberg (2005). https://doi.org/10.1007/978-3-540-32033-3_22Cremers, C.J.F.: The scyther tool: verification, falsification, and analysis of security protocols. In: Gupta, A., Malik, S. (eds.) CAV 2008. LNCS, vol. 5123, pp. 414–418. Springer, Heidelberg (2008). https://doi.org/10.1007/978-3-540-70545-1_38Dreier, J., Duménil, C., Kremer, S., Sasse, R.: Beyond subterm-convergent equational theories in automated verification of stateful protocols. In: Maffei, M., Ryan, M. (eds.) POST 2017. LNCS, vol. 10204, pp. 117–140. Springer, Heidelberg (2017). https://doi.org/10.1007/978-3-662-54455-6_6Escobar, S., Hendrix, J., Meadows, C., Meseguer, J.: Diffie-Hellman cryptographic reasoning in the Maude-NRL protocol analyzer. In: Proceedings of 2nd International Workshop on Security and Rewriting Techniques (SecReT 2007) (2007)Escobar, S., Meadows, C., Meseguer, J.: A rewriting-based inference system for the NRL protocol analyzer and its meta-logical properties. Theor. Comput. Sci. 367(1–2), 162–202 (2006)Escobar, S., Meadows, C., Meseguer, J.: Maude-NPA: cryptographic protocol analysis modulo equational properties. In: Aldini, A., Barthe, G., Gorrieri, R. (eds.) FOSAD 2007-2009. LNCS, vol. 5705, pp. 1–50. Springer, Heidelberg (2009). https://doi.org/10.1007/978-3-642-03829-7_1Escobar, S., et al.: Protocol analysis in Maude-NPA using unification modulo homomorphic encryption. In: Proceedings of PPDP 2011, pp. 65–76. ACM (2011)Escobar, S., Meadows, C.A., Meseguer, J., Santiago, S.: State space reduction in the Maude-NRL protocol analyzer. Inf. Comput. 238, 157–186 (2014)Escobar, S., Sasse, R., Meseguer, J.: Folding variant narrowing and optimal variant termination. J. Log. Algebr. Program. 81(7–8), 898–928 (2012)Fabrega, F.J.T., Herzog, J.C., Guttman, J.D.: Strand spaces: why is a security protocol correct? In: Proceedings of IEEE Symposium on Security and Privacy, pp. 160–171 (1998)Guttman, J.D.: Security goals and protocol transformations. In: Mödersheim, S., Palamidessi, C. (eds.) TOSCA 2011. LNCS, vol. 6993, pp. 130–147. Springer, Heidelberg (2012). https://doi.org/10.1007/978-3-642-27375-9_8Joux, A.: A one round protocol for tripartite Diffie-Hellman. In: Bosma, W. (ed.) ANTS 2000. LNCS, vol. 1838, pp. 385–393. Springer, Heidelberg (2000). https://doi.org/10.1007/10722028_23Kim, Y., Perrig, A., Tsudik, G.: Communication-efficient group key agreement. In: Dupuy, M., Paradinas, P. (eds.) SEC 2001. IIFIP, vol. 65, pp. 229–244. Springer, Boston, MA (2002). https://doi.org/10.1007/0-306-46998-7_16Küsters, R., Truderung, T.: Using ProVerif to analyze protocols with Diffie-Hellman exponentiation. In: IEEE Computer Security Foundations, pp. 157–171 (2009)Küsters, R., Truderung, T.: Reducing protocol analysis with XOR to the XOR-free case in the horn theory based approach. J. Autom. Reason. 46(3–4), 325–352 (2011)Meadows, C.: The NRL protocol analyzer: an overview. J. Logic Program. 26(2), 113–131 (1996)Meier, S., Cremers, C., Basin, D.: Strong invariants for the efficient construction of machine-checked protocol security proofs. In: 2010 23rd IEEE Computer Security Foundations Symposium, pp. 231–245 (2010)Meseguer, J.: Conditional rewriting logic as a united model of concurrency. Theoret. Comput. Sci. 96(1), 73–155 (1992)Meseguer, J.: Variant-based satisfiability in initial algebras. Sci. Comput. Program. 154, 3–41 (2018)Meseguer, J.: Generalized rewrite theories, coherence completion, and symbolic methods. J. Log. Algebr. Meth. Program. 110, 100483 (2020)Mödersheim, S., Viganò, L.: The open-source fixed-point model checker for symbolic analysis of security protocols. In: Aldini, A., Barthe, G., Gorrieri, R. (eds.) FOSAD 2007-2009. LNCS, vol. 5705, pp. 166–194. Springer, Heidelberg (2009). https://doi.org/10.1007/978-3-642-03829-7_6Sasse, R., Escobar, S., Meadows, C., Meseguer, J.: Protocol analysis modulo combination of theories: a case study in Maude-NPA. In: Cuellar, J., Lopez, J., Barthe, G., Pretschner, A. (eds.) STM 2010. LNCS, vol. 6710, pp. 163–178. Springer, Heidelberg (2011). https://doi.org/10.1007/978-3-642-22444-7_11Schmidt, B., Sasse, R., Cremers, C., Basin, D.A.: Automated verification of group key agreement protocols. In: 2014 IEEE Symposium on Security and Privacy, SP 2014, pp. 179–194. IEEE Computer Society (2014)Skeirik, S., Meseguer, J.: Metalevel algorithms for variant satisfiability. J. Log. Algebraic Methods Program. 96, 81–110 (2018)TeReSe: Term Rewriting Systems. Cambridge University Press, Cambridge (2003)Yang, F., Escobar, S., Meadows, C.A., Meseguer, J., Narendran, P.: Theories of homomorphic encryption, unification, and the finite variant property. In: Proceedings of PPDP 2014, pp. 123–133. ACM (2014

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool

Aims: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. Methods: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. Results: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as ‘discrepant but noncontributory’. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). Conclusions: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information

Mutations in Potassium Channel KCND3 Cause Spinocerebellar Ataxia Type 19

OBJECTIVE: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. METHODS: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. RESULTS: We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory β subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. INTERPRETATION: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

Protocol analysis modulo combination of theories: A case study in Maude-NPA

There is a growing interest in formal methods and tools to analyze cryptographic protocols modulo algebraic properties of their underlying cryptographic functions. It is well-known that an intruder who uses algebraic equivalences of such functions can mount attacks that would be impossible if the cryptographic functions did not satisfy such equivalences. In practice, however, protocols use a collection of well-known functions, whose algebraic properties can naturally be grouped together as a union of theories E 1... ¿ n. Reasoning symbolically modulo the algebraic properties E 1... ¿ n requires performing (E 1... ¿ n)-unification. However, even if a unification algorithm for each individual E i is available, this requires combining the existing algorithms by methods that are highly non-deterministic and have high computational cost. In this work we present an alternative method to obtain unification algorithms for combined theories based on variant narrowing. Although variant narrowing is less efficient at the level of a single theory E i, it does not use any costly combination method. Furthermore, it does not require that each E i has a dedicated unification algorithm in a tool implementation. We illustrate the use of this method in the Maude-NPA tool by means of a well-known protocol requiring the combination of three distinct equational theories. © 2011 Springer-Verlag.R. Sasse and J. Meseguer have been partially supported by NSF Grants CNS0716638, CNS-0831064 and CNS-0904749. S. Escobar has been partially supported by the EU (FEDER) and the Spanish MEC/MICINN under grant TIN 2007-68093- C02-02. C. Meadows has been partially supported by NSF Grant CNS-0904749National Science Foundation, EEUUSasse, R.; Escobar Román, S.; Meadows, C.; Meseguer, J. (2011). Protocol analysis modulo combination of theories: A case study in Maude-NPA. En Security and Trust Management. Springer Verlag (Germany). 6710:163-178. doi:10.1007/978-3-642-22444-7_11S1631786710Abadi, M., Cortier, V.: Deciding knowledge in security protocols under equational theories. Theoretical Computer Science 367(1-2), 2–32 (2006)Armando, A., Basin, D.A., Boichut, Y., Chevalier, Y., Compagna, L., Cuéllar, J., Drielsma, P.H., Héam, P.-C., Kouchnarenko, O., Mantovani, J., Mödersheim, S., von Oheimb, D., Rusinowitch, M., Santiago, J., Turuani, M., Viganò, L., Vigneron, L.: The avispa tool for the automated validation of internet security protocols and applications. In: Etessami, K., Rajamani, S.K. (eds.) CAV 2005. LNCS, vol. 3576, pp. 281–285. Springer, Heidelberg (2005)Baader, F., Schulz, K.U.: Unification in the union of disjoint equational theories: Combining decision procedures. In: Kapur, D. (ed.) CADE 1992. LNCS, vol. 607, pp. 50–65. Springer, Heidelberg (1992)Basin, D.A., Mödersheim, S., Viganò, L.: An on-the-fly model-checker for security protocol analysis. In: Snekkenes, E., Gollmann, D. (eds.) ESORICS 2003. LNCS, vol. 2808, pp. 253–270. Springer, Heidelberg (2003)Baudet, M., Cortier, V., Delaune, S.: YAPA: A generic tool for computing intruder knowledge. In: Treinen, R. (ed.) RTA 2009. LNCS, vol. 5595, pp. 148–163. Springer, Heidelberg (2009)Blanchet, B.: An efficient cryptographic protocol verifier based on prolog rules. In: CSFW, pp. 82–96. IEEE Computer Society, Los Alamitos (2001)Bursuc, S., Comon-Lundh, H.: Protocol security and algebraic properties: Decision results for a bounded number of sessions. In: Treinen, R. (ed.) RTA 2009. LNCS, vol. 5595, pp. 133–147. Springer, Heidelberg (2009)Chevalier, Y., Küsters, R., Rusinowitch, M., Turuani, M.: An NP decision procedure for protocol insecurity with XOR. In: LICS, pp. 261–270. IEEE Computer Society, Los Alamitos (2003)Chevalier, Y., Rusinowitch, M.: Hierarchical combination of intruder theories. Inf. Comput. 206(2-4), 352–377 (2008)Chevalier, Y., Rusinowitch, M.: Symbolic protocol analysis in the union of disjoint intruder theories: Combining decision procedures. Theor. Comput. Sci. 411(10), 1261–1282 (2010)Ciobâcă, Ş., Delaune, S., Kremer, S.: Computing knowledge in security protocols under convergent equational theories. In: Schmidt, R.A. (ed.) CADE-22. LNCS, vol. 5663, pp. 355–370. Springer, Heidelberg (2009)Comon-Lundh, H., Delaune, S.: The finite variant property: How to get rid of some algebraic properties. In: Giesl, J. (ed.) RTA 2005. LNCS, vol. 3467, pp. 294–307. Springer, Heidelberg (2005)Cortier, V., Delaitre, J., Delaune, S.: Safely composing security protocols. In: Arvind, V., Prasad, S. (eds.) FSTTCS 2007. LNCS, vol. 4855, pp. 352–363. Springer, Heidelberg (2007)Cremers, C.J.F.: The scyther tool: Verification, falsification, and analysis of security protocols. In: Gupta, A., Malik, S. (eds.) CAV 2008. LNCS, vol. 5123, pp. 414–418. Springer, Heidelberg (2008)Escobar, S., Meadows, C., Meseguer, J.: A rewriting-based inference system for the NRL protocol analyzer and its meta-logical properties. Theoretical Computer Science 367(1-2), 162–202 (2006)Escobar, S., Meadows, C., Meseguer, J.: Maude-NPA: Cryptographic protocol analysis modulo equational properties. In: Aldini, A., Barthe, G., Gorrieri, R. (eds.) FOSAD 2007/2008/2009 Tutorial Lectures. LNCS, vol. 5705, pp. 1–50. Springer, Heidelberg (2009)Escobar, S., Meseguer, J., Sasse, R.: Effectively checking or disproving the finite variant property. Technical Report UIUCDCS-R-2008-2960, Department of Computer Science - University of Illinois at Urbana-Champaign (April 2008)Escobar, S., Meseguer, J., Sasse, R.: Effectively checking the finite variant property. In: Voronkov, A. (ed.) RTA 2008. LNCS, vol. 5117, pp. 79–93. Springer, Heidelberg (2008)Escobar, S., Meseguer, J., Sasse, R.: Variant narrowing and equational unification. Electr. Notes Theor. Comput. Sci. 238(3), 103–119 (2009)Escobar, S., Sasse, R., Meseguer, J.: Folding variant narrowing and optimal variant termination. In: Ölveczky, P.C. (ed.) WRLA 2010. LNCS, vol. 6381, pp. 52–68. Springer, Heidelberg (2010)Fabrega, F.J.T., Herzog, J., Guttman, J.: Strand Spaces: What Makes a Security Protocol Correct? Journal of Computer Security 7, 191–230 (1999)Guo, Q., Narendran, P.: Unification and matching modulo nilpotence. In: CADE-13. LNCS, vol. 1104, pp. 261–274. Springer, Heidelberg (1996)Harkins, D., Carrel, D.: The Internet Key Exchange (IKE), IETF RFC 2409, (November 1998)Jouannaud, J.-P., Kirchner, C., Kirchner, H.: Incremental construction of unification algorithms in equational theories. In: Díaz, J. (ed.) ICALP 1983. LNCS, vol. 154, pp. 361–373. Springer, Heidelberg (1983)Küsters, R., Truderung, T.: Reducing protocol analysis with xor to the xor-free case in the Horn theory based approach. In: ACM Conference on Computer and Communications Security, pp. 129–138 (2008)Küsters, R., Truderung, T.: Using ProVerif to analyze protocols with Diffie-Hellman exponentiation. In: CSF, pp. 157–171. IEEE Computer Society, Los Alamitos (2009)Lafourcade, P., Terrade, V., Vigier, S.: Comparison of cryptographic verification tools dealing with algebraic properties. In: Degano, P., Guttman, J.D. (eds.) FAST 2009. LNCS, vol. 5983, pp. 173–185. Springer, Heidelberg (2010)Lowe, G.: Breaking and fixing the Needham-Schroeder public-key protocol using FDR. In: Margaria, T., Steffen, B. (eds.) TACAS 1996. LNCS, vol. 1055, pp. 147–166. Springer, Heidelberg (1996)Meadows, C.: The NRL protocol analyzer: An overview. J. Log. Program. 26(2), 113–131 (1996)Meseguer, J.: Conditional rewriting logic as a united model of concurrency. Theor. Comput. Sci. 96(1), 73–155 (1992)Meseguer, J.: Membership algebra as a logical framework for equational specification. In: Parisi-Presicce, F. (ed.) WADT 1997. LNCS, vol. 1376, pp. 18–61. Springer, Heidelberg (1998)Meseguer, J., Thati, P.: Symbolic reachability analysis using narrowing and its application to verification of cryptographic protocols. Higher-Order and Symbolic Computation 20(1–2), 123–160 (2007)Ohlebusch, E.: Advanced Topics in Term Rewriting. Springer, Heidelberg (2002)Santiago, S., Talcott, C.L., Escobar, S., Meadows, C., Meseguer, J.: A graphical user interface for Maude-NPA. Electr. Notes Theor. Comput. Sci. 258(1), 3–20 (2009)Schmidt-Schauß, M.: Unification in a combination of arbitrary disjoint equational theories. J. Symb. Comput. 8(1/2), 51–99 (1989)Terese (ed.): Term Rewriting Systems. Cambridge University Press, Cambridge (2003)Turuani, M.: The CL-atse protocol analyser. In: Pfenning, F. (ed.) RTA 2006. LNCS, vol. 4098, pp. 277–286. Springer, Heidelberg (2006

Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney complex. Recently, we described the presence of activating codon 209 mutations in the GNAQ gene in primary leptomeningeal melanocytic lesions. Identical codon 209 mutations have been described in blue nevi. The aims of the present study were to (1) perform a histological review of a series of lesions (initially) diagnosed as melanotic schwannoma and analyze them for GNAQ mutations, and (2) test the diagnostic value of GNAQ mutational analysis in the differential diagnosis with leptomeningeal melanocytic lesions. We retrieved 25 cases that were initially diagnosed as melanotic schwannoma. All cases were reviewed using established criteria and analyzed for GNAQ codon 209 mutations. After review, nine cases were classified as melanotic schwannoma. GNAQ mutations were absent in these nine cases. The remaining cases were reclassified as conventional schwannoma (n = 9), melanocytoma (n = 4), blue nevus (n = 1) and lesions that could not be classified with certainty as melanotic schwannoma or melanocytoma (n = 2). GNAQ codon 209 mutations were present in 3/4 melanocytomas and the blue nevus. Including results from our previous study in leptomeningeal melanocytic lesions, GNAQ mutations were highly specific (100%) for leptomeningeal melanocytic lesions compared to melanotic schwannoma (sensitivity 43%). We conclude that a detailed analysis of morphology combined with GNAQ mutational analysis can aid in the differential diagnosis of melanotic schwannoma with leptomeningeal melanocytic lesions

Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies

Integrin α7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice.

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7-/- mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7-/- mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7-related congenital myopathy