We found that some mutations occurred only in tumor tissue and not in blood cells (n=5). In these instances, the mutations are called somatic mutations. For genetic counseling purposes, parents and family members of patients with somatic mutations do not need to be tested because there are no implications for inheritance. The TP53 mutations we found in this group include R175H, R273C, R273H, V218M, and c.134_135 insT. All of them were observed in a heterozygous state and are reported in IARC database (http://www.iarc.fr/). We did not observe loss of heterozygosity (LOH) in these cases, and p53 protein was found in all cases by IHC.
We observed germline TP53 mutations in 26 cases. Our analyses revealed the mutation was inherited in 12 cases. Of the 12 cases with an inherited TP53 mutation, 6 cases – all from Brazil – carried the R337H mutation, the most prevalent TP53 mutation registered in the IARC database. In addition to R337H, other inherited mutations include R337C, R248W, and two complex TP53 mutations, IVS10-2A/G and c.108_110 dupl GTTTCCG. We found TP53 mutations in germline blood DNA in 5 pediatric adrenocortical tumor (ACT) cases; however, the mutations were not present in parental blood DNA. This indicates that these 5 patients had a de novo mutation, and are therefore considered to be the first family member that harbors a TP53 mutation. Their descendants can inherit the mutated allele and predisposition for cancer development; therefore, genetic counseling is advised. The mutations observed in this group included nonsense mutations R196X, E285V, R282W, I332F, and 375 +1 G>A. In 9 germline cases, we could not determine whether there was an inheritance pattern because we did not have blood samples from parents. Mutations seen in this group included R273C, R175L, R213Q, G266E, R158L, R175H, R283H, G245C, and a complex mutation c51_53 del CAAT ins GACCTG. LOH was determined in 18 cases.
In 7 ACT cases, we only had blood samples available for testing, and all of them revealed a WT TP53 sequence. However, we could not exclude the possibility of a somatic TP53 mutation. In the other 5 cases, we only tested tumor samples, and we observed a TP53 mutation in all of them. At this time, we do not know if these mutations are somatic or germline mutations.
The following table is a summary of the observed TP53 status in our cohort after the IPACTR phase 2 amendment:
|TP53 mutation||Number of cases|
Physicians and researchers at St. Jude have performed additional studies in several adrenocortical tumor cases, including RNA expression, copy number variation, whole genome sequencing, and xenograft model (West, Neale et al. 2007).