Li-Fraumeni Syndrome Support Group

The incidence of Adrenocortical Tumors(ACT) in Southern Brazil is 10 times higher than that of the general population.  ACT, usually diagnosed in childhood, has been linked to Li Fraumeni Syndrome and a mutation in the p53 chromosome region.  Dr. Raul Ribeiro found that despite the high incidence of ACT, the families in the southern regions of Brazil did not show an increased diagnosis of other core tumors seen in typical LFS. These families presented a unique opportunity to study Adrenocortical carcinoma, the potential relation to the p53 mutation and the case for newborn screening of this condition.

Maria Isabel Achatz spoke at the conference about a special group of Brazilian families with a high occurrence of adrenal tumors.  Over 40 children were studied to try and find the relationship between their genetics and the high incidence of ACT. Since ACT account for over 50% of childhood tumors that present in typical LFS families, it was a surprise that these families in Brazil did not appear to have a higher rate of other cancers. There is no tumor registry in Brazil, so it is uncertain what the true numbers are.  Upon analysis, these children were found to have a mutation in the 337^th codon of the p53 region,  Arginine to histidine(R337H).  The hope is to further study the relation of this mutation to fully understand it’s potential role in ACT development and loss of p53 function.

In 2007, a more comprehensive study was done looking into the relation between R337H and other cancers.  It was found in not only breast cancers in Brazil, but a wide spectrum of tumors. When residents without a high incidence of cancers were studied, they did not have a higher rate of mutated R337H. This supported that the TP53 Mutation R337H was associated with Li Fraumeni Syndrome and Li Fraumeni Like Syndromes in Brazilian families.  A big discovery was that although the tumor spectrum was similar, there were some major differences.  There seemed to be a higher occurrence of Renal and Thyroid cancers among the Brazilian population of LFS kindreds.  A model of partial penetrance(why some genes are expressed and others aren’t) was studied to better understand why the Brazilian families showed a varying tumor spectrum than other regions.

Since the R337H mutation is correlated with not only ACT, which presents usually during childhood, it is also linked to a predisposition for other cancers. This provides a solid case to consider Newborn Screening protocols in the southern region of Brazil. This presents several challenges, especially considering the ethical ramifications of screening asymptomatic patients. In 2008, the Southern State of Parana began debating a screening regimen for newborns.  One main controversy is the inability to predict where or when the cancer may develop.  Studies have progressed to determine if screening is worth the financial, emotional and physical burdens of diagnosis.

Another study looked into a possible Founder Effect. Studies have indicated that despite LFS kindreds in Brazil’s apparently not being related, the high incidence of R337H mutation does indicate a common ancestor and their possible migration pattern. Founder effect is seen when there is little genetic variation within a certain population.  It is estimated that 1/300 within the Brazilian population are carriers of the R337H mutation.

Pierre Hainaut discussed the various Genotype/Phenotype correlations of p53 mutations, which the Brazilian families had a big part in elucidating. He found that different mutations within the p53 region result in different expression of the syndrome. Genotype is what the genes say should be expressed, phenotype is what is actually seen.  Some mutations result in earlier age of onset, there is also  a biphasic diagnosis of tumors- some seen commonly in childhood and then a latency period until adulthood. The majority of mutations are missense, which means one codon is mutated, changing the amino acid it codes for. This one codon changes whether or not the p53 protein can work. There are many pathways that have yet to be discovered that will tell us why certain mutations cause certain cancers.  Research in such areas will help improve diagnostic screening and possible therapies.  There is an IARC database for p53 mutations which helps researchers share various work on the multitude of mutations that seem to plague that region of genetic code.