2008 Barcelona - European Society of Human Genetics

Cancer genetics
to both control groups; therefore, the presence of multiple LOH in a
sample of cfDNA could predicate lung cancer . LOH of D5S299 had
the highest sensitivity, and D5S346 (both in the vicinity of APC gene)
had the highest specifity of all used primers. In the lung cancer group,
there were two patients where one of two alleles of D5S82 or D5S318,
respectivelly, completely disappeared; this was not seen in any individual
in both control groups .
Supported by MSMT CR MSM0021620808
P04.158
M6P/IGF 2R is mutated in human endometrial adenocarcinomas
and lung cancer
J. Pavelic;
Rudjer Boskovic Institute, Zagreb, Croatia.
The M6P/IGF 2 receptor has been shown to be mutated in a number
of human cancers and to suppress cancer cell growth, indicating it as
a tumor suppressor . The aim of this study was to determine if the M6P/
IGF 2R is a target for mutation in human endometrial and lung cancers,
tumors where perturbation of level of IGF’s peptides seems to be
implicated in neoplastic growth by autocrine/paracrine mechanisms .
The tumors were analyzed for loss of heterozygosity (LOH) . In those
with LOH at one M6P/IGF 2R locus, the remaining allele was screened
for mutation in ligand binding region by direct sequencing of PCR products
. Among 10 informative adenocarcinoma samples 4 had LOH at
M6P/IGF 2R locus . Of them, two samples harbored the mutation in
the remaining allele as well . Of 46 endometrial adenocarcinomas 16
had LOH at one IGF 2R locus . The remaining allele in 8 of these samples
contained also the mutation in the IGF 2 binding domain . As IGF
2R mediate activation of the growth inhibitor TGF-b and clearance of
growth promoter IGF 2, whose down and up regulation are involved in
malignant transformation, it is reasonable to believe that dysfunction of
IGF 2R by mutation, could also contribute to tumor development .
P04.159
candidate gene screening for melanoma susceptibility
C. Badenas 1,2 , J. Puig Butille 2 , M. Harland 3 , Z. Ogbah 4 , R. Cervera 2 , J. Malvehy
5,2 , M. Milà 1,2 , T. Bishop 3 , S. Puig 5,2 ;
1 Biochemical and Molecular Genetics Service. Hospital Clinic, Barcelona,
Spain, 2 Centro Investigación Biomédica en Enfermedades Raras (CIBERER),
ISCIII, Barcelona, Spain, 3 Genetic Epidemiology Division, St. James’s University
Hospital, Leeds, United Kingdom, 4 Fundacio Clinic per a la Recerca Biomedica,
Barcelona, Spain, 5 Dermatology Department, Melanoma Unit. Hospital
Clinic, Barcelona, Spain.
Melanoma is a multifactorial and polygenic disease . The main risk
factors are number of nevi, familial predisposition and skin phototype
related to ultraviolet radiation exposition . Ten percent of cases are
detected in a familial setting, being then inherited as an autosomal
dominant trait . Two high susceptibility genes have been implicated:
CDKN2A/p14ARF and CDK4 . Mutations are detected in 20-60% of
families . Nevertheless, sporadic melanoma accounts for 90% of cases
. The molecular basis of melanoma predisposition in such patients
has not been well characterized .
Aim: i) to determine the real implication of CDKN2A and CDK4 in sporadic
melanoma and to evaluate the clinical differences between mutation
carriers and non-carriers . ii) Genotyping of 265 SNPs (located in
38 genes) to look for low susceptibility genes implicated in melanoma
and nevus predisposition .
696 melanoma patients have been screened for CDKN2A and CDK4
mutations . SNP genotyping has been carried out in 260 melanoma
patients using the GenomeLab SNPstream Genotyping System .
Sixteen sporadic Melanoma patients are CDKN2A mutation carriers
(2 .3%) . Mutations are more frequent in multiple melanoma (MPM) than
in single primary patients (SPM) (12 .2% vs 1%, p=0 .000) . Age at onset
is lower in mutation carriers than non-carriers (36 .63 vs 50 .63 y .o,
p=0,001) . A148T variant has been detected in 14 .6% of patients with
MPM and in 7 .2 of SPM (p=0 .02), suggesting that A148T could act as
a low susceptibility allele to melanoma predisposition . Results of SNP
genotyping are being analized and data will be discussed .
Acknowledgements: FISS: 03-0019, 05-0302 .
P04.160
Germline mutations of CDKN2A in multiple and familial
melanoma Brazilian kindreds
A. L. R. Avila 1,2 , J. P. D. Neto 3 , G. Landmann 2 , D. M. Carraro 1 ;
1 Laboratory of Genomic and Molecular Biology of Treatment and Investigation
Center of Hospital A.C.Camargo, Sao Paolo, Brazil, 2 Department of Pathology
of Hospital A.C. Camargo, Sao Paolo, Brazil, 3 Department of Cuteneous Oncology
of Hospital A.C. Camargo, Sao Paolo, Brazil.
Background: Melanoma is hereditary in approximately 10% of cases .
Familial melanoma is described as a family in which either 2 first-degree
relatives are diagnosed with melanoma, or families with 3 melanoma
patients (irrespective of degree of relationship) . CDKN2A is the
first identified and the most important melanoma susceptibility gene.
The mutation spectrum in the Brazilian population is unknown .
Aim: Report our experience in screening of mutations of CDKN2A gene
in Brazilian kindreds with clinical diagnosis of Familial Melanoma . This
study is part of the Melanoma Genetics Consortium, (GenoMEL) in
Latin America .
Methods: Patients with multiple or familial clustering of Melanoma were
genetically tested. Families were identified applying the GenoMEL diagnosis
criteria . Point mutations in CDKN2A gene were screened by
denaturing high performance liquid chromatography (DHPLC) followed
by direct sequencing .
Results: Genomic DNA of 12 patients with clinical diagnosis of familial
melanoma was obtained from peripheral blood samples . CDKN2A
gene was divided into 9 fragments covering the 4 exons with substantial
parts of intron regions . Blood sample was collected from one adult
healthy control that not presented mutation in CDKN2A gene and it is
used as a reference for DHPLC experiment .
P04.161
MC R polymorphisms, phenotype and UVB radiation sensitivity
in melanoma risk patients
P. Aguilera 1 , C. Carrera 1 , G. Salerni 1 , F. Cuellar 1 , Z. Ogbah 2 , J. A. Puig-Butille 2 ,
M. Lecha 3 , J. Malvehy 1 , S. Puig 1 ;
1 Melanoma Unit, Barcelona, Spain, 2 Melanoma Unit, Genetic Service, Barcelona,
Spain, 3 Photobiology and Phototherapy Unit, Dermatology Service,
Barcelona, Spain.
Background: UV radiation (UVR) plays an important role in melanocytic
tumours development . History of intense intermittent sun-exposure,
phenotypic characteristics encoding melanocortin-1 receptor
gene (MC1R) and the presence of multiple nevi are risk markers to
develop malignant melanoma . Familiar melanoma represents 10% of
all melanomas and it is supposed that genetic burden in these patients
plays a more important role than environmental factors .
Objective: to study in different melanoma-risk patient settings the association
between phenotypic characteristics, number of nevi, UVR
sensitivity and polymorphisms in MC1R .
Methods: two groups of high risk melanoma patients were studied
(N=32):
Group 1: Dysplastic nevus syndrome (DNS) patients (N=23) .
Group 2: Melanoma patients belonging to familial melanoma (N=9) .
UVB sensitivity, phenotypic and genotypic characterization were performed
.
Results: patients from DNS had a higher UV-B photosensitivity (reduced
UV-B minimal erythemal dose) compared with patients from
familiar melanoma group (mean 88mJ/cm2± 26 vs 122 mJ/cm2 ± 26;
p