Genetica si îngrijirea personalizata in cancer

A V-a editie a Conferintei Asociatiei Melanom Romania Inovatia in Melanom- Viata este un drept pentru TOTI, Bucuresti, 24-25 iunie 2022

Genetica si ingrijirea personalizata in melanom 

Elena Emanuela Braha



Medic primar genetica medicala Medic specialist endocrinologie

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Cancerul = problema majora de sanatate publica pe plan mondial, cu diferenţe semnificative in morbiditate / mortalitate, factorii de risc, strategia de preventie si accesul la tratament / ingrijiri Depistare precoce + tratament individualizat  sanse de vindecare Sunt 3 tipuri majore de cancer cutanat: -Bazal (BCC – basal cell cancer) provin din keratinocite - Scuamos (SCC) -Melanom - provine din melanocite (Erb, Ji, Kump, Mielgo, & Wernli, 2008)

BCC + SCC = non-melanoma skin cancer (NMSC)

NMSC  – diagnosticate precoce au prognostic bun comparativ cu melanomul  BCC se dezvolta local, rar MTS  SCC tinde sa metastazeze (Gordon, 2013) BCC  Asociat cu dereglarea caii de semnalizare sonic hedgehog (Athar, Li, Kim, Spiegelman, & Bickers, 2014) SCC  Mutatii in gena p53 (Emmert, Schön, & Haenssle, 2014)  Mutatii RAS, pl6INK4a cu o frecventa mai mica (Emmert et al., 2014; Xie, 2008).

Melanomul = o forma de cancer cu punct de plecare in melanocite  la nivelul pielii, ochiului, mucoasei canalului anal, rectului, vaginului - reprezinta mai putin de 5% din toate cazurile de cancer cutanat - este responsabil de majoritatea deceselor datorate cancerului cutanat - daca nu este depistat precoce si tratat, melanomul poate metastaza la ganglionii limfatici si la organelor interne. Plamanii si ficatul sunt tinte frecvente.

EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (2016): -

In Europa 1/100 persoane vor dezvolta melanom candva in cursul vietii

-

In fiecare an sunt tratati 19 250 de pacienti cu melanom metastazat

http://www.esmo.org/Conferences/Past-Conferences/ESMO-2016-Congress/Press-Media/Thousands-of-M elanoma-Patients-in-Europe-Have-no-Access-to-New-Life-Saving-Drugs

“din 2020 până în 2040, cazurile noi de melanom cutanat vor crește cu ~ 50%”

https://www.iarc.who.int/news-events/global-burden-of-cutaneous-melanoma-in-2020-and-projections-to-2040/

Epidemiologie 1-3% din toate neoplasmele [Rigel DS et al, 1996] Incidenta melanomului la caucazieni este in crestere [Lens MB et al, 2004]  Cea mai agresiva forma de cancer de piele (5% din neo cutanate) 75% din decesele datorate Neo cutanat [Siegel 

R et al, 2014]

Apare la orice varsta (rar la copii); cancerul cel mai frecvent diagnosticat la persoane < 30 ani [Bleyer A et al, 2006]  ~ 30-40% dintre tumori metastazeazã în ganglionii limfatici regionali, plaman, ficat, intestine, maduva osoasa, creier (originea embriologica comuna a melanocitelor si neuronilor) [De la Monte SM et al, 1983]  10% cazuri MTS este diagn inaintea tumorii primare [Anbari 

KK et al, 1997]



Diagnostic precoce  tratament!!

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29. doi: 10.3322/caac.21208. Epub 2014 Jan 7. Erratum in: CA Cancer J Clin. 2014 SepOct;64(5):364.

Rigel DS, Friedman RJ, Kopf AW. Lifetime risk for development of skin cancer in the U.S. population: current estimate is now 1 in 5. J Am Acad Dermatol. 1996 Dec;35(6):1012-3.

Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol. 2004 Feb;150(2):179-85.

Bleyer A, Viny A, Barr R. Cancer in 15- to 29-year-olds by primary site. Oncologist. 2006 Jun; 11(6):590-601.

De la Monte SM, Moore GW, Hutchins GM. Patterned distribution of metastases from malignant melanoma in humans. Cancer Res. 1983;43:3427-33.

Factori de mediu = Radiații ultraviolet (UVR)  deteriorarea ADN [Vink AA et al, 2001] Factori de risc intrinseci = fenotipul pacientului (pielea albă, păr blond sau roşcat, ochi albaştri, pistrui + nu se bronzeaza + numar crescut de nevi cutanati) + gene de susceptibilitate/ predispozitie Istoricul familial  5- 12% melanoame apar in context familial [Ransohoff, K. J et al 2016; .

Read, J., et aal 2015]

 45%c se datoreaza unei mutatii mostenite, inalt penetrante (gena de susceptibilitate)  55% aparent lipseste transmiterea <- mutatie cu penetranta redusa + polimorfism genic + factori mediu 1. Vink AA, Roza L. Biological consequences of cyclobutane pyrimidine dimers. J Photochem Photobiol B. 2001 Dec 31; 65(2-3):101-4.

2. Ransohoff, K. J., Jaju, P. D., Tang, J. Y., Carbone, M., Leachman,S.,& Sarin, K. Y. (2016). Familial skin cancer syndromes increased melanoma risk. Journal of the American Academy of Dermatology, 74(3), 423–434. doi:10.1016/j.jaad.2015.09.070.

3. Read, J., Wadt, K. A. W., & Hayward, N. K. (2015). Melanoma genetics. Journal of Medical Genetics, 53, 1–14. doi:10.1136/jmedgenet-2015-103150.

1. Genele de susceptibilitate la melanom (mutatii germinale)

Zocchi L, Lontano A, Merli M, Dika E, Nagore E, Quaglino P, Puig S, Ribero S. Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management. J Clin Med. 2021 Aug 23;10(16):3760. doi: 10.3390/jcm10163760. PMID: 34442055; PMCID: PMC8397216.

1. Genele de susceptibilitate la melanom (mutatii germinale)

1.1.Gene de risc inalt = gene mutante care confera individului un risc inalt de a face boala + asociate cu existenta melanoamelor multiple in familie

1. Genele de susceptibilitate la melanom (mutatii germinale) 1.1.Gene de risc inalt CDKN2A (Cyclin-dependent kinase inhibitor 2A) – cea mai frecv o localizata 9p21 codifica 2 proteine supresoare de tumori p16INK4A si p14ARF (prin cadru de citire alternativ si splicing diferentiat) [Aoude LG et al, 2015] o ~ 20% din melanoamele familiale (cu variatii de 5 – 72% depinzand de aria geografica si criteriile de selectie) [Goldstein AM et al, 2007] o Mai frecv in familiile cu numar mare de cazuri sau la pac cu melanom primar multiplu sporadic [Auroy S et al, 2001] o Corelat cu varsta tanara la momentul diagnosticului o Indivizii purtaturi ai mutatiei germinale CDKN2A au risc de a dezvolta cancer pancreatic [Potrony M et al, 2014] o Mutatiile familiale  risc crescut de cancer de san, pulmonar, cancere induse de fumat , astrocitom[Helgadottir H et al, 2014; Potrony M et al, 2014] o “rule of 3”: 3 melanoame/ 1 melanom + 2 rude grad 1 cu melanom/ ca pancreatic  TESTARE

Recomandarea testelor genetice – incidenta melanomului in zona geografica , istoricul familial, varsta de debut, asocierea cu alte neoplasme

Bruno W., Pastorino L., Ghiorzo P., Andreotti V., Martinuzzi C., Menin C., Elefanti L., Stagni C., Vecchiato A., Rodolfo M., et al. Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup. J. Am. Acad. Dermatol. 2016;74:325–332.

Zocchi L, Lontano A, Merli M, Dika E, Nagore E, Quaglino P, Puig S, Ribero S. Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management. J Clin Med. 2021 Aug 23;10(16):3760. doi: 10.3390/jcm10163760. PMID: 34442055; PMCID: PMC8397216.

1. Genele de susceptibilitate la melanom (mutatii germinale) 1.1.Gene de risc inalt = gene mutantate care confera individului un risc inalt de a face boala + asociate cu existenta melanoamelor multiple in familie -

BAP1 (Breast cancer BRCA1 associated protein 1) o BAP1 tumor predisposition syndrome (BAP1-TPDS) = sindrom recent descris  predispozitie la melanom uveal, mesoteliom malign, melanom cutanat, carcinoma renal, alte cancere (carcinoma bazocelular, neoplasm pulmonar, cancer de san/ovar, tumori neuroendocrine, sarcom) [H. Helgadottir et al, 2016; Babak Masoomian Jerry et al, 2018] o Cancere agresive, varsta tanara o 90% anamneza fam pozitiva o Un individ poate avea mai mult de un tip de cancer primar + nev Spitz, melanom cutanat sau uveal, mesoteliom, carcinoma renal cu cellule clare.

[Potrony M et al, 2015]

Puntervoll HE, Yang XR, Vetti HH, Bachmann IM, Avril MF, Benfodda M, Catricalà C, Dalle S, Duval-Modeste AB, Ghiorzo P, Grammatico P, Harland M, Hayward NK, Hu HH, Jouary T, Martin-Denavit T, Ozola A, Palmer JM, Pastorino L, Pjanova D, Soufir N, Steine SJ, Stratigos AJ, Thomas L, Tinat J, Tsao H, Veinalde R, Tucker MA, Bressac-de Paillerets B, Newton-Bishop JA, Goldstein AM, Akslen LA, Molven A. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013 Apr; 50(4):264-70.

1.2. Gene cu risc scazut / moderat Melanocortin 1 Receptor (MC1R) – 16q24 Inalt polimorfa in populatia caucaziana Regleaza pigmentarea cutanata, codifica α melanocyte-stimulating hormone (α-MSH) receptor 1 Mutatiile MC1R varianta R (p.D84E, p.R142H, p.R151C, p.I155T, p.R160W, p.D294H)  creste cantitate feomelanina (pigment red – yellow) creste riscul de melanom [Williams PF et al, 2011] Riscul este aditiv (indiv cu 2 alele R au un risc de 4-6 ori mai mare comparative cu indivizii fara) MITF (Microphthalmia-associated transcription factor) – 3p14 Rol in dezvoltarea si diferentierea melanocitelor Varianta functionala p.E318K (rs149617956) asociata cu piele deschisa la culoare, nevi multipli  risc crescut de melanom [Yokoyama S et al, 2011]

Sindroame cu melanom (“melanoma subordinate syndromes” 

Variantele patogene ale genelor asociate cu melanom pot predispune si la aparitia altor tipuri de cancer



Aceste sindroame se por manifesta ca melanom – dominante (mutatii CDKN2A, BAP1) sau ca melanomasubordinate Cele mai frecvente sdr melanoma subordinate: xeroderma pigmentosum (multiple XP genes), sdr. Li Fraumeni (TP53 mutations), sindromul Cowden (PTEN mutations)



Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H. Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol. 2016;74:395–407.

Truderung, O. A., Sagi, J. C., Semsei, A. F., & Szalai, C. (2021). Melanoma susceptibility: an update on genetic and epigenetic findings. International journal of molecular epidemiology and genetics, 12(5), 71– 89.

1. Mutatii germinale  susceptibilitatea la dezv melanomului 2. Cancere familiale cu risc crescut de melanoma 3. Mutatii somatice  terapie tintita  sindromul Li-Fraumeni = prevalenta 1-9/100.000 indv ( www.orpha.net) transm AD, mutatie germinala p53; cancer de san + sarcom osos/ parti moi + tumori cerebrale + tumori de suprarenala + rar melanom [CurielLewandrowski C et al, 2011]  xeroderma pigmentosum – AR, rara (1/1.000.000 pers – orphaned) mutatii in genele de reparare a ADN (DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, XPC), clinic = fotosensibilitate, melanom, cancere cutanate derivate din celulele bazale sau scuamoase, tumori sistem nervos [Bradford PT et al, 2011]

 Sindromul Cowden - genodermatoza AD, asociaza tumori benigne (hamartoame, papule orale, risc crescut de a dezvolta neoplazii Raportate mutatii in gena PTEN (10q23) - PTEN hamartoma tumor syndrome (PHTS) group.

 familial atypical multiple mole-melanoma (FAMMM syndrome) - cancer pancreatic + nevi multipli + melanom Raportate mutatii in gena p16 (CDKN2A)

 Melanoma-Astrocytoma Syndrome (MAS) – pierderea functiei p14ARF -Alterari ale cromozomului 9p21 inclusiv ale clusterului de gene CDKN2A/CDKN2B/CDKN2BAS -Transmitere AD -Penetranta crescuta -Expresivitate variabila -Clinic melanoame cutanate maligne + tumori SNC CDKN2A are o structura genica unica in genomul uman Exonul 1 are 2 forme alternative 1a si 1b  doua cadre de lectura diferite  doua proteine diferite functional p16 si p14ARF

Ce facem? 

  

Tendinta actuala pentru cancere familiale/ melanom familial  multi-gene panel tests (datorita riscului de a dezvolta si alte tumori) Stim mutatia la proband  putem opta pentru secventiere tintita Esential sfatul genetic pre si post-testare Pacietii sa inteleaga/ sa accepte si riscul de a avea un rezultat neclar (VUS, posibil patogen) – limitele tehnicii si a datelor stiintifice din momentul testarii

Truderung, O. A., Sagi, J. C., Semsei, A. F., & Szalai, C. (2021). Melanoma susceptibility: an update on genetic and epigenetic findings. International journal of molecular epidemiology and genetics, 12(5), 71–89.

Leachman SA, Lucero OM, Sampson JE, Cassidy P, Bruno W, Queirolo P, Ghiorzo P. Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev. 2017 Mar;36(1):77-90.

De interes! Polygenic risk scores (PRS) 

  

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genome-wide association studies (GWAS) a identificat mii de loci posibil patogeni cu susceptibilitate scazuta pentru melanoma Raportate 11 – 204 SNVs Aceaste riscuri se pot aduna Apare posibilitatea calcularii unui risc poligenic prin insumarea riscurilor pentru fiecare gena in parte  posibil aplicabilitate clinica pentru a imbunatati predictia A fost propus un risc care utilizeaza cel mai frecvent 11 – 45 SNVs

Soura E, Stratigos A. Implementing polygenic risk scores in skin cancer: a step towards personalized risk prediction. Br J Dermatol. 2019;181:1117–1118. [PubMed] [Google Scholar] Zhang YD, Hurson AN, Zhang H, et al; Breast Cancer Association Consortium (BCAC); Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON); Colon Cancer Family Registry (CCFR); Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT); Endometrial Cancer Association Consortium (ECAC); Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); Melanoma Genetics Consortium (GenoMEL); Glioma International Case-Control Study (GICC); International Lung Cancer Consortium (ILCCO); Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium; International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph); Ovarian Cancer Association Consortium (OCAC); Oral Cancer GWAS; Pancreatic Cancer Case-Control Consortium (PanC4); Pancreatic Cancer Cohort Consortium (PanScan); Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL); Renal Cancer GWAS; Testicular Cancer Consortium (TECAC) Chanock SJ, Chatterjee N, Garcia-Closas M. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun. 2020;11:3353.

Roberts MR, Asgari MM, Toland AE. Genome-wide association studies and polygenic risk scores for skin cancer: clinically useful yet? Br J Dermatol. 2019;181:1146–1155.

3. Mutatii somatice (dobandite)

MAPK pathway inhibitors = RAS/RAF/MEK/ERK patway. RAS activation promotes the formation of RAF dimers. RAF phosphorylates MEK, which upon activation phosphorylates ERK. ERK regulates both cytosolic targets and nuclear transcription factors, thus promoting proliferation, survival, and other hallmarks of transformation.

http://cancerdiscovery.aacrjournals.org/content/3/7/719

2.1.Proto-oncogena BRAF (v-raf murine sarcoma viral oncogene homolog B1)  7q34, 18 exoni  serin/treonin protein-kinaza din familia kinazelor Raf implicată în calea de semnalizare intracelulară Ras/Raf/MEK/ERK (MAPK/ERK )  Cea mai frecventa mutatie somatica din melanom (~ 50% din melanoame) = mutatia activatoare BRAFV600 [Davies H et al, 2002]  hiperstimularea caii MAPK/MEK mitogen-activated protein kinase mitoze!  mutatii activatoare V600E (valina  ac glutamic), V600K, V600R, V600D  TESTARE!  Inhibitori BRAF!!! – sorafenib, Vemurafenib (pt V600E) si Dabrafenib ( pt V600E, V600K) , Trametinib

 15% pacienti au mecanism intrinsic de rezistenta la inhibitorii BRAF (“reactivation of the MAPK pathway is the most frequent cause of acquired/secondary resistance” ) [Spagnolo F et al, 2015]

2.1.2. - Inhibitorii MEK  Trametinib si cobimetinib  combinatia de inhibitori BRAF/inhibitor MEK este de preferat fata de inhibitor BRAF în monoterapie, [http://www.ascopost.com/issues/april-10-2018/encorafenib-plus-binimetinib-inbraf-melanoma/ ]

2.2. NRAS (neuroblastoma RAS viral v-ras oncogene)  Membru al familiei oncogenelor RAS  15-20% din melanoame au mutatie NRAS [Padua RA et al, 1984]  activarea proteinei RAS  imposibilitatea de a cliva GTP  stimuleaza diviziunea celulara  Mutatiile NRAS mai frecvente in pielea expusa cronic la soare [Curtin JA, Fridlyand J et al, 2005]  Mutatii agresive, rata crescuta a mitozelor  Mutatiile BRAF si NRAS se exclud una pe alta [Goel VK et al, 2006]  In studiu “direct RAS-targeted therapy” in cancerul pulmonary - allele-specific inhibitors, Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov.

2020 Aug;19(8):533-552. doi: 10.1038/s41573-020-0068-6. Epub 2020 Jun 11. Erratum in: Nat Rev Drug Discov. 2020 Dec;19(12):902. PMID: 32528145; PMCID: PMC7809886.

2.2. NRAS (neuroblastoma RAS viral v-ras oncogene)

Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov.

2020 Aug;19(8):533-552. doi: 10.1038/s41573-020-0068-6. Epub 2020 Jun 11. Erratum in: Nat Rev Drug Discov. 2020 Dec;19(12):902. PMID: 32528145; PMCID: PMC7809886.

2.3. NF1 (neurofibromin 1)

 Mutatiile NF1 (m inactivatoare) afecteaza >12% din toate melanoamele; frecv reg cap - gat  Cel mai frevent in melanoame BRAF si RAS wild-type (WT) [Krauthammer et al., 2015; The Cancer Genome Atlas Network, 2015]  Raspund la terapie imunologica

Thielmann CM, Chorti E, Matull J, Murali R, Zaremba A, Lodde G, Jansen P, Richter L, Kretz J, Möller I, Sucker A, Herbst R, Terheyden P, Utikal J, Pföhler C, Ulrich J, Kreuter A, Mohr P, Gutzmer R, Meier F, Dippel E, Weichenthal M, Paschen A, Livingstone E, Zimmer L, Schadendorf D, Hadaschik E, Ugurel S, Griewank KG. NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors. Eur J Cancer.

2021 Dec;159:113-124. doi: 10.1016/j.ejca.2021.09.035. Epub 2021 Nov 4. PMID: 34742158.

2.4. C-Kit (proto-oncogene c-Kit, CD117)  Proteina de suprafata cu rol de receptor tirozin-kinazic  Mutatiile activatoare melanomului, tumorilor gastrointestinale, LAM leucemie acuta mieloida, seminom etc. TERAPIE! imatinib (Gleevec) si nilotinib (Tasigna)  Frecvent in melanoamele acrale, mucoase si in pielea expusa cronic la soare https://www.skincancer.org/ publications/the-melanomaletter/winter-2011-vol-29-no.3/ targeting-kit

In melanomul mucoaselor      

Mutatii germinale: BAP1, rar p53 Cele mai frecvente mutatii somatice raportate SF3B1 (27%), KIT (18%), NF1 (17%) SF3B1 este raportat mai frecvent la pacientii cu melanoma ◦ ano-rectal > vulvovaginal, nazofaringian; prognostic neclar ◦ Uveal, relativ neresponsiv la trat imunologic dar cu prognostic favorabil

Hajkova, N., Hojny, J., Nemejcova, K. et al. Germline mutation in the TP53 gene in uveal melanoma. Sci Rep 8, 7618 (2018). https://doi.org/10.1038/s41598-018-26040-0 Buchbinder EI, Weirather JL, Manos M, et al. Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade. Cancer Med. 2021;10(8):2627-2635. doi:10.1002/cam4.3789 Harbour JW, Roberson EDO, Anbunathan H, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet. 2013;45(2):133‐135 Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes.

JAMA Ophthalmol. 2016;134(7):728‐733.

Newell F, Kong Y, Wilmott JS, Johansson PA, Ferguson PM, Cui C, Li Z, Kazakoff SH, Burke H, Dodds TJ, Patch AM, Nones K, Tembe V, Shang P, van der Weyden L, Wong K, Holmes O, Lo S, Leonard C, Wood S, Xu Q, Rawson RV, Mukhopadhyay P, Dummer R, Levesque MP, Jönsson G, Wang X, Yeh I, Wu H, Joseph N, Bastian BC, Long GV, Spillane AJ, Shannon KF, Thompson JF, Saw RPM, Adams DJ, Si L, Pearson JV, Hayward NK, Waddell N, Mann GJ, Guo J, Scolyer RA. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets. Nat Commun. 2019 Jul 18;10(1):3163. doi: 10.1038/s41467-019-11107-x. PMID: 31320640; PMCID: PMC6639323.

WGS  mutatiilor somatice din melanomul mucoasei  raporteaza frecvent rearanjamente structural care au ca tinta genele TERT, CDK4, MDM2, NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX 

TERT si ATRX sunt asociate cu afectarea telomerelor  Mutatia SF3B1 raportata frecvent la melanomul mucoasei genitale feminine 



Profilul mutatiilor MM sugereaza un potential terapeutic al inhibitorilor MEK sau imunoterapia

Melanomul uveal   



 

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Cea mai frecventa tumora maligna a ochiului Tip rar de melanoma Cea mai frecv mutatie germinala – BAP1 (1.6 – 3% pacienti) –> Neo diverse, MTS, transmitere AD Mutatii somatice : EIF1AX, GNA11, GNAQ, si SF3B1  progresie si prognostic Adesea este diagn in stadiul cu MTS hepatice Rezistent la chimioterapi clasica, nu are mutatii BRAF Imunoterapie (immune checkpoint inhibitors), inhibitori MEK in tumorile GNAQ/GNA11

Helgadottir, H., & Höiom, V. (2016). The genetics of uveal melanoma: current insights. The application of clinical genetics, 9, 147–155. https://doi.org/10.2147/TACG.S69210

Melanom conjunctival   



25 – 30% mutatii somatice BRAF V600E Alte gene somatice: TERT, NRAS, NF1 Raportata o suprapunere peste genetica melanomului cutanat TERT  MTS

van Poppelen, N.M.; de Bruyn, D.P.; Bicer, T.; Verdijk, R.; Naus, N.; Mensink, H.; Paridaens, D.; de Klein, A.; Brosens, E.; Kiliҫ, E. Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing. Int. J. Mol. Sci. 2021, 22, 336. https://doi.org/10.3390/ijms22010336

Ce testam in tumora?

Melanom cutanat

  

imunohistochimie = expresia genica Mutatiile din celulele tumorale SNP array ◦ Castig/ pierdere de material genetic

van Poppelen, N.M.; de Bruyn, D.P.; Bicer, T.; Verdijk, R.; Naus, N.; Mensink, H.; Paridaens, D.; de Klein, A.; Brosens, E.; Kiliҫ, E. Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing. Int. J. Mol. Sci. 2021, 22, 336. https://doi.org/10.3390/ijms22010336

Ce testam in M ocular? 

IHC = expresia genica

Absenta expresiei BAP1 = risc MTS inalt

 

FISH cu sonde dedicate SNP array

◦ Monosomia crz 3 asociata cu m BAP1 ◦ Castig de material genetic 8q = prognostic sever ◦ Pierdere 1p, castig pe crz 6



Mutatii somatice

van Poppelen, N.M.; de Bruyn, D.P.; Bicer, T.; Verdijk, R.; Naus, N.; Mensink, H.; Paridaens, D.; de Klein, A.; Brosens, E.; Kiliҫ, E. Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing. Int. J. Mol. Sci. 2021, 22, 336. https://doi.org/10.3390/ijms22010336

EIF1AX

Xp22 Implicata in 14%– initierea

21%

translocatie cazuri i

SF3B1

2q33 Esentiala pentru clivare

10%– 24%

Se exclude

Mutatii

reciproc

exon 1 si

cu mutatiile

BAP1 si EIF1AX .

Asociere – prognostic bun Se exclude reciproc

cu mutatiile

2, status

heterozig ot

Status

heterozig ot

BAP1 si Hot spot EIF1AX . in Asociere – v codonul tanara, MTS Arg625 Helgadottir, H., & Höiom, V. (2016). The genetics of uveal melanoma: current insights. The application of clinical tardiv genetics, 9, 147–155. https://doi.org/10.2147/TACG.S69210 ARNm

NAQ

9q21

Intervine in calea

28%– 50%

MAPK

Se exclude

reciproc cu

Mutatii in codonul

mutatiile GNA11 . Glu209 si Considerat ca un

Arg183

eveniment precoce

Fara corelatie cu prognosticul

GNA11 19p13 Intervine in calea MAPK

32%–

Se exclude

Mutatii in

50%

reciproc cu

codonul

mutatiile GNAQ . Glu209 si Considerat ca un eveniment

Arg183

Helgadottir, H., & Höiom, V. (2016). The genetics of uveal melanoma: current insights. The application of clinical genetics, 9, 147–155. https://doi.org/10.2147/TACG.S69210

precoce

! Teste neinvazive 

Folosite frecvent pentru diagnostic si monitorizare



Include cell free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTC), tumor-derived exosomes, tumor-educated platelets si micro-RNA.

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Pacientii cu CTCs detectate in stadiile precoce ale melanomului uveal au un prognostic mai rezervat

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La cei cu melanom uveal + MTS – CTC si nivelul ctDNA sunt de asemenea corelate cu diametrul tumorii, numarul/ volumul metastazelor, progresia bolii si supavietuirea

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Mutatiile GNAQ si GNA11 au fost raportate in ctDNA la pacientii cu melanom uveal

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Rata de detectie ctDNA este mai scazuta la pacientii cu melanom uveal localizat comparative cu cei cu MTS

1.Anand, K.; Roszik, J.; Gombos, D.; Upshaw, J.; Sarli, V.; Meas, S.; Lucci, A.; Hall, C.; Patel, S. Pilot Study of Circulating Tumor Cells in Early-Stage and Metastatic Uveal Melanoma. Cancers 2019, 11, 856.

2.Bidard, F.C.; Madic, J.; Mariani, P.; Piperno-Neumann, S.; Rampanou, A.; Servois, V.; Cassoux, N.; Desjardins, L.; Milder, M.; Vaucher, I.; et al. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int. J. Cancer 2014, 134, 1207–1213.

3.Aaron, B.; Timothy, I.; Muhammad, A.K.; James, B.F.; Richard, A.; Fred, K.C.; Michelle, R.P.; Kyle, Y.; Jaqueline, B.; Tersia, V.; et al. Clinical Application of Circulating Tumor Cells and Circulating Tumor DNA in Uveal Melanoma. JCO Precis. Oncol. 2018, 2, 1–12.

Boyer M, Cayrefourcq L, Dereure O, Meunier L, Becquart O, AlixPanabières C. Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma. Cancers. 2020; 12(4):960.

Zhao EY, Bratman SV. Emerging Precision Oncology Applications of Liquid Biopsy using Circulating Tumour DNA and Methylome Profiling. Clin Oncol (R Coll Radiol). 2020 Oct;32(10):626-631.

Comprehensive Genomic Profiling/ profilarea comprehensiva genomica Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples Scott A. Tomlins, Daniel H. Hovelson, Jennifer M. Suga, Daniel M. Anderson, Han A. Koh, Elizabeth C. Dees, Brendan McNulty, Mark E. Burkard, Michael Guarino, Jamil Khatri, Malek M. Safa, Marc R. Matrana, Eddy S. Yang, Alex R. Menter, Benjamin M. Parsons, Jennifer N. Slim, Michael A. Thompson, Leon Hwang, William J. Edenfield, Suresh Nair, Adedayo Onitilo, Robert Siegel, Alan Miller, Timothy Wassenaar, William J. Irvin, William Schulz, Arvinda Padmanabhan, Vallathucherry Harish, Anneliese Gonzalez, Abdul Hai Mansoor, Andrew Kellum, Paul Harms, Stephanie Drewery, Jayson Falkner, Andrew Fischer, Jennifer Hipp, Kat Kwiatkowski, Lorena Lazo de la Vega, Khalis Mitchell, Travis Reeder, Javed Siddiqui, Hana Vakil, D. Bryan Johnson, and Daniel R. Rhodes JCO Precision Oncology 2021 :5, 1312-1324

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Se poate efectua in tesutul tumoral sau in ctDNA (biopsie lichida)

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La pacientii in stadii avansate ale bolii

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Evalueaza mutatiile in genele raportate in literature, SNV, ins/del mici, CNV, gene de fuziune, instabilitatea microsatelitilor, sarcina mutationala tumorala (nr de modificari genetice din celula tumorala) - tumor mutation burden

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Poate ghida personalizat tratamentul

O modalitate de prevenire a bolii valoarează cât cincizeci de moduri de a vindeca boala.

Trevor Howard

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Elena Emanuela Braha

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Medic primar genetica medicala Medic specialist endocrinologie

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