cdkn2a, cdk4, mc1r gēnu izmaiņas melanomas

8/9/2019 CDKN2A, CDK4, MC1R gēnu izmaiņas melanomas

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CDKN2A, CDK4, MC1R gnu izmaiasmelanomas slimniekiem ar melanomas,aizkua dziedzera vai smadzeuaudzja saslimanas gadjumiem

imens Latvij.Darbu veidoja: Kristne Azarjana, Aija Ozola, Dace Pjanova, Ingrda ma,

Regna Kleina, Ludmila Eele, Baiba treinerte, Olita Heisele

RSU ZINTNISK KONFERENCE2010. Gada 18. UN 19. marts

Krista Grigorovia 4.gr, MFII



Ievads

Augsta riska melanomas gni ± CDKN2A

un CDK4 , tie ir iesaistti nas cikla

regulcij. Zema riska melanomas gns - MC1R



Darba mris

Izanalizt CDKN2A, CDK4, MC1R gnusmelanomas slimniekiem ar atkrtotiem

melanomas gadjumiem imens, k ar pacientiem, kuriem imens ir saslimanas gadjumi ar smadzeu vaiaizkua dziedzera audzju.



Materils un metodes

Ptjum tika iekauti 25 melanomas slimnieki, kuriemimenes anamnz bija melanoma, aizkua dziedzeravai smadzeu audzjs.

No asins paraugiem tika izdalta DNS ar standarta fenola

± hloroforma metodi. Ar PCR tika pavairoti CDKN2A gna visi eksoni, CDK4gna 2. eksons un viss MC1R gns.

Produktu sintze tika prbaidta ar agarozes glaelektroforzi.

Reakcijas produktus attrja izmantojot garnelessrmaino fosfatzi un eksanuklezi 1 Sekvenjot izmantoja BigDay sekvenanas kitu un

analizja uz ABI PRISM 3100 gnu analizatora



Rezultti

2

8

6

5

4

3 un vairk melanomas gadjumi

melanoma kdam no pirms pakpes radiniekiem

ar melanomu slimojui attlki radinieki (2.-3.pak.)

dadi smadzeu audzji (1. pakpes radinieki)

aizkua dziedzera audzjs (2gadjumos -1.pakpes un 2 gadjumos attlkiemradiniekiem)



Rezultti

Analizjot CDKN2A gnu mutcijas netikaatrastas. Bet tika atrastas atsevii gnapolimorfismi ± A148T (n=1), c.*29C>G(n=4), c.*69C>T (n=3), par, kuru lomumelanomas attstb ir pretrungi dati.



Rezultti

CDK4 gna mutcija R24H tika atrastadiviem pacientiem, kuru imens bija pa 5melanomas saslimanas gadjumiemkatr.



Rezultti

MC1R gna analz tika atrasti :

13 pacientiem - V60L, R160W, V92M,

T314T, R151C, R142H, R163Q, S316Spolimorfismi

Diviem pacientiem atrada trs MCR1 gnapolimorfismus

etriem pacientiem ± 2

Seiem pacientiem ± 1



0

5

10

15

20

25

CDKN2A CDK4 MC1R

M

m m



Secinjumi

Melanomas prmantojamba imens ar 2melanomas saslimanas gadjumiem, k ar imens ar spordisku melanomu un smadzeu

vai aizkua dziedzera audzju nav saistta ar mutcijm CDKN2A un CDK4 gnos. imens ar vairkiem melanomas gadjumiem

melanoma prmantojas saistb ar CDK4 gna

R24H mutciju. Dadie MC1R gna polimorfismi norda uzmint gna iespjamo lomu melanomasattstb, kas btu jpierda plak ptjum.



Int J Cancer. 1997 Feb 20;74(1):26-30. p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression. Piccinin S, Doglioni C, Maestro R, Vukosavljevic T, Gasparotto D, D'Orazi C, Boiocchi M. Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy. Abstract The p16/CDKN2(MTS1) gene encoding for the p16 inhibitor of cyclin D/CDK4 complexes is

frequently mutated and deleted in a large fraction of melanoma cell lines, and p16 germline

mutations have also been observed in familial melanomas. Moreover, a CDK4 gene mutation,responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity, has beendescribed to occur in some cases of familial melanoma. These data strongly support the idea thatderegulation of the CDK4/cyclin D pathway, via CDKN2 or CDK4 mutations, is of biologicalsignificance in the development of melanoma. To shed light on the role of these alterations in thedevelopment and progression of sporadic melanoma, 12 primary melanomas and 9 correspondingmetastases were analyzed for CDKN2 and CDK4 gene mutations. Of the 12 primary melanomasanalyzed, 4 showed the presence of mutational inactivation of the p 16 protein and 2 carried silentmutations. No metastases showed the presence of CDKN2 mutations, indicating that mutations of this cyclin-dependent kinase inhibitor is not common in the progression of sporadic melanoma. Onthe other hand, the absence, in the metastases, of the CDKN2 mutation detected in thecorresponding primary tumors suggests that 9p21 homozygous deletion may play a major role inthe metastatic spreading of this type of tumor. None of the cases analyzed showed the presenceof an Arg24Cys mutation, which functionally protects CDK4 from p16 inhibition. This indicates thatCDK4 mutation plays a minor role in the development and progression of sporadic melanoma.

http://www.ncbi.nlm.nih.gov/pubmed/9036865



MC1R variants increase melanoma risk in families with CDKN2A mutations: A

meta-analysis. 2010 Feb 26

Fargnoli MC, Gandini S, Peris K, Maisonneuve P, Raimondi S.

Department of Dermatology, University of L'Aquila, L'Aquila, Italy.

Ptjuma mris: Ms veicm meta-analzi, lai novrttu, vai MC1R polimorfismspalielina risku melanomas CDKN2A mutciju nesjiem melanomas imenm.

REZULTTI: CDKN2A mutciju nesjiem ar 1 MC1R variantu bija dubutlielsmelanomas risks, saldzinot ar CDKN2A mutciju nesjiem bez MC1R variantiem

Secinjums: MC1R varianti ievrojami palielina penetranci CDKN2A gna mutcijmmelanomas varbtbai pakautm imenm, jo pai attiecb uz vairkiem MC1R

variantiem un RVC variantiem. Liela nozme melanomas diagnostik tiek novrotaCDKN2A mutciju nesjiem ar MC1R variantiem.

http://www.ncbi.nlm.nih.gov/sites/entrez



Citu autoru darbiPredicting functional significance of cancer-associated p16(INK4a) mutations

in CDKN2A. 2010 Mar 25 McKenzie HA, Fung C, Becker TM, Irvine M, Mann GJ, Kefford RF, Rizos H.

Westmead Institute for Cancer Research and Melanoma Institute of Australia,University of Sydney at Westmead Millennium Institute, Westmead Hospital,Westmead NSW 2145, Australia.

Mantots mutcijas, kas ietekm INK4a/ARF lokusu (CDKN2A) gn, tiek asocitas

ar melanomas jutgumu 40% no vairkiem gadjumiem melanomu imens. Vairknek 60 dadas germ-line INK4a/ARF mutcijas tika konstattas vairk nek 190imeu vis pasaul. o izmaiu lielk daa ir missense mutciju, kas ietekmp16INK4a.

http://www.ncbi.nlm.nih.gov/sites/entrez



MC1R common variants, CDKN2A and their association with melanoma and breast cancer risk

DEBNIAK Tadeusz; SCOTT Rodney; MASOJC Barttomiej; SERRANO-FERNANDEZ Pablo; HUZARSKI Tomasz;BYRSKI Tomasz; DEBNIAK Boguslaw; GORSKI Bohdan; CYBULSKI Cezary; MEDREK Krzysztof;KURZAWSKI Grzegorz; VAN DE WETERING Thierry; MALESZKA Romuald; KADNY Jozef ; LUBINSKI Jan ;

We sought to examine the association between MC1R variants and the risk of melanoma and breast cancer inPolish population. We also determined the prevalence of compound heterozygous carriers of MC1R and CDKN2A( A148T) variants. We examined 500 unselected melanoma cases, 511 consecutive invasive breast cancer patients, 800 newborns, 421 healthy adults matched for sex and age with the melanoma cases and 511 healthywomen matched for sex and age with the breast cancer cases. A statistically significant association of all 4 MC1Rvariants with the melanoma risk was found. For the R151C variant p value was 0.000008 and odds ratio 2.9; for the V60L variant p value was 0.007 and OR 1.78; for the R160C p was 0.006 and OR 1.76; for the R163Q p was0.015 and odds ratio 2.1. None of the compound heterozygotes were significantly over-represented among any of the melanoma cases, the highest OR (4.2) observed in patients harbouring the A148T variant in CDKN2A and theR151C variant in MC1R. Positive association was found between carrying any of the MC1R variants and (i)increased occurrence of melanoma among I degree relatives of the carriers; (ii) increased occurrence of melanoma on UV-non-exposed skin areas. We also observed a tendency of increased risk of multiple melanomasamong carriers of MC1R variants. The haplotype analysis demonstrates that MC1R variants do not co-occur in cis,compound carriers have both alleles affected. We found no association with the MC1R variants and breast cancer

risk. In conclusion, the results of this population-based study show herein that MC1R variants are associated withincreased melanoma risk in the Polish population. The risk of disease seems to be increased additively for patientsharbouring also the CDKN2A common variant A148T.

International journal of cancer ISSN 0020-7136 CODEN IJCNAW http://cat.inist.fr/?aModele=afficheN&cpsidt=18251102



Pasaul katru gadu konstat 130 000 melanomu gadjumu,

aptuveni 37 000 cilvku katru gadu no audzja mirst http://www.euromelanoma.lv/lv/articles/view/melanoma/melanomas-izplatiba



Izmantot literatra

http://www.ncbi.nlm.nih.gov/pubmed/9036865

http://cat.inist.fr/?aModele=afficheN&cpsidt=18251102

cdkn2a, cdk4, mc1r gēnu izmaiņas melanomas

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