2008 Barcelona - European Society of Human Genetics

Cancer genetics
P04.012
A novel PtEN mutation in an italian family with hyperplastic
polyposis of the colon in the context of cowden syndrome
D. Turchetti 1,2 , L. M. Pradella 1 , C. Rossi 1 , A. Alberani 3 , F. Ferrara 3 , P. A. Fanti 4 ,
G. Romeo 1 ;
1 UO e Cattedra di Genetica Medica - Azienda Ospedaliero-Universitaria Policlinico
S.Orsola-Malpighi, Bologna, Italy, 2 Dipartimento di Oncologia - Presidio
Ospedaliero Bellaria-Maggiore, Bologna, Italy, 3 UO Gastroenterologia ed Endoscopia
Digestiva - Presidio Ospedaliero Bellaria-Maggiore, Bologna, Italy, 4 UO
Dermatologia - Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Clinical manifestations of Cowden Syndrome, which is caused by mutations
in the PTEN gene, are extremely variable . Among gastrointestinal
manifestations, hamartomatous polyps are the typical lesions, but
other polyp types, including hyperplastic, have been reported .
We describe a family in which hyperplastic polyposis was the reason
for referral to the genetic clinic and that was found to carry a novel
PTEN mutation .
The proband, a 46 year-old man, was referred to the cancer genetic
clinic because of the endoscopic finding of colonic polyposis. Histology
showed the polyps to be hyperplastic . Moreover, upper gastrointestinal
endoscopy detected esophageal acanthosis and papillomatosis and
HP-related gastritis . Physical examination revealed the presence of
macrocephaly (65cm), obesity and cutaneous papillomas . The mother,
62 year-old, had also been diagnosed with hyperplastic polyposis and
with carcinoma ex-adenoma of the left colon, for which had undergone
hemicolectomy at age 61 . Previously, she had had hysterectomy for
uterine fibroids at age 47 and mastectomy for invasive ductal carcinoma
of the breast at age 51 . Physical examination showed macrocephaly
(59cm), obesity, cutaneous papillomas and subcutaneous
lipomas .
PTEN mutational analysis in the proband revealed the germline heterozygous
mutation 303delA in the exon 5, which was confirmed in the
mother . This mutation, which to our knowledge has never been described
before, generates a stop at codon 111, producing a truncated
protein which looses three functionally relevant domains .
To help clarify the pathogenic mechanism of the mutation, we are now
performing molecular studies on pathologic tissues removed from the
patients .
P04.013
Dysregulation of RAs signaling in colorectal carcinomas
I. Bottillo 1 , I. Torrente 1 , T. Ahlquist 2 , S. A. Danielsen 2 , G. I. Meling 3 , R. A.
Lothe 2 , B. Dallapiccola 1,4 ;
1 CSS-Mendel Institute, Rome, Italy, 2 Department of Cancer Prevention, Institute
for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo,
Norway, 3 Surgical Department, Faculty Division Akershus University Hospital,
University of Oslo, Oslo, Norway, 4 Department of Experimental Medicine, Sapienza
University, Rome, Italy.
Half of all colorectal carcinomas (CRC) have dysregulation of the RAS
signaling, increasing the cellular proliferative potential and resistance
to apoptosis . KRAS is known to be commonly mutated in CRC, while
mutational status of the NF1 gene, acting as a negative regulator of
RAS signaling, is not known . We analyzed a series of CRC for mutations
in KRAS, BRAF, and NF1 . NF1 coding region screening was
performed by dHPLC (denaturing high performance liquid chromatography),
sequencing and MLPA (multiple ligation-dependent probe
amplification). KRAS and BRAF were analyzed by sequencing . 40%
(26/65) of the samples carried a mutation in KRAS, 22% (14/64) in
BRAF, and 13% (3/24) in NF1 . We found that 62% (40/65) of the samples
had alterations in one or more of the components, meaning they
have a dysregulation of the RAS pathway . BRAF and KRAS mutations
were mutually exclusive . BRAF mutation was strongly associated with
microsatellite instability (MSI), female gender, and proximal location .
Among the 24 samples analyzed for mutations in NF1, we found 2
missense and 2 splicing mutations . All NF1 mutations occurred in MSI,
proximal, and female-derived tumors with BRAF mutation . In addition,
we found that 3 of the samples had duplication of parts or the whole
NF1 gene . In conclusion RAS pathway is dysregulated by mutually
exclusive mutations of KRAS and BRAF in the majority of CRC . We
show that the activity of RAS signaling is likely to be enhanced in more
than 10% of the tumors since they harbor mutations in both BRAF and
NF1 .
P04.014
Age related differences in molecular profiles of colorectal
cancers in patients from the Republic of macedonia
M. Hiljadnikova - Bajro 1 , T. Josifovski 2 , A. Kapedanovska 1 , Z. Serafimoska 1 ,
Z. Sterjev 1 , N. Matevska 1 , M. Panovski 2 , N. Petrusevska 2 , L. Suturkova 1 , A. J.
Dimovski 1 ;
1 Faculty of Pharmacy, Skopje, The former Yugoslav Republic of Macedonia,
2 Faculty of Medicine, Skopje, The former Yugoslav Republic of Macedonia.
Colorectal cancer (CRC) is considered a disease of elderly, though
2-3% occurs in patients G (p .H1047R) in 3 cases . We also found c .3073 A>G
(p .T1025A) and c .3145 G>C (p .G1049R) . In one case we found a mutation
which, to our knowledge, has not been reported previously: c .
3074 C>T (p .T1025I) .
Two of the patients with exon 20 PIK3CA mutations had metastatic disease
(33%), while 3 of 54 (5 .5%) patients with no mutations had metastasis
(p=0 .07) . The mean age at diagnosis for patients with PIK3CA
mutation was 62 .8, and for patients without a mutation - 63 .3 .
Somatic mutations in exon 20 of PIK3CA have been shown to be oncogenic
as they lead to an increased PI3K activity . The PI3K regulate
signaling pathways such as cell proliferation, survival and adhesion .
Our results confirm that PIK3CA alterations may play an important role