<a name="home"></a>The P48T germline mutation and polymorphism in the CDKN2A gene of patients with melanoma

Abstract

CDKN2A has been implicated as a melanoma susceptibility gene in some kindreds with a family history of this disease. Mutations in CDKN2A may produce an imbalance between functional p16 ink4a and cyclin D causing abnormal cell growth. We searched for germline mutations in this gene in 22 patients with clinical criteria of hereditary cancer (early onset, presence of multiple primary melanoma or 1 or more first-or second-degree relatives affected) by secondary structural content prediction, a mutation scanning method that relies on the propensity for single-strand DNA to take on a three-dimensional structure that is highly sequence dependent, and sequencing the samples with alterations in the electrophoretic mobility. The prevalence of CDKN2A mutation in our study was 4.5% (1/22) and there was a correlation between family history and probability of mutation detection. We found the P48T mutation in 1 patient with 2 melanomaaffected relatives. The patient descends from Italian families and this mutation has been reported previously only in Italian families in two independent studies. This leads us to suggest the presence of a mutational "hotspot" within this gene or a founder mutation. We also detected a high prevalence (59.1%) of polymorphisms, mainly alleles 500 C/G (7/31.8%) or 540 C/T (6/27.3%), in the 3' untranslated region of exon 3. This result reinforces the idea that these rare polymorphic alleles have been significantly associated with the risk of developing melanoma. Correspondence

DoCDKN2 p16 540 C>G,CDKN2 p16 580 C>T, andMDM2 SNP309 T>GGene Variants Act on Colorectal Cancer Development or Progression?

“…It was known that the loss of function in p16 results in the inactivation of its growth suppressor effect (Shapiro et al, 1995). Until today the mutations of p16 gene were investigated in many studies (Shapiro et al, 1995;McCloud et al, 2004) and controversial results about cancer development were reported especially for the 3¢ UTR region (Kumar et al, 2001;Huber and Ramos, 2006;Larre et al, 2009;Ibarrola-Villava et al, 2010). Accordingly, in the present study, the evaluation of the possible association of CDKN2 p16 540C > G and/or CDKN2 p16 580C > T polymorphisms with the clinical and pathological parameters as well as the development of CRC was aimed.…”

Clinical genetic testing for familial melanoma in Italy: A cooperative study

“…The most frequent mutations were G101W (in 41 families, 60%), R24P (in 5 families, 7%), P48T (in 5 families, 7%), and E27X (in 4 families, 6%). Thus, although the G101W founder mutation accounted for roughly 60% of all the mutations identified (41/68 families), a further 23% is accounted for by other welldocumented (E27X 8 , G23S 9 ) or potential founder (P48T 21,22 ) mutations, or recurring mutations (R24P 10 ). Three novel mutations, L94P, A86T, and c.407dupG, were identified among the cases and not in 200 controls.…”

Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene

“…This investigation revealed the P48T mutation located in exon 1. This mutation has been described in three Italian melanoma families (35)(36)(37), and, recently, in a multiple primary melanoma patient from Hungary, suggesting that a common founder, either in Italy or Hungary, may be present (38). This mutation also predisposes to pancreatic cancer (39,40), although the mechanism is still debated, and has been previously described in one Italian patient with pancreatic cancer (40).…”