Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome: clinical and genetic study in a series of Spanish patients

Abstract

Background: The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease.

Results: We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research.

Conclusions: This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.

Keywords: Cowden syndrome; Exome; NGS; PTEN gene; PTEN hamartoma tumor syndrome.

Fig. 1

PTEN pathogenic variants found in our series. A PTEN point variants: numbers, distribution and types. B PTEN protein domains affected by the exonic variants. C Schematic representation of the gene regions affected by each of the 7 large deletions involving PTEN

Fig. 2

Proportion of individuals showing the indicated clinical manifestations in our series. A Occurrence of benign clinical features. B Occurrence of the different cancer types (not linked to sex). C Occurrence of sex-linked cancer types. PHTS-associated cancer types are boxed. Chi-square or Fisher test significance (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001) is shown for comparisons of absolute numbers of the PTEN-wt and PTEN-mut groups

Fig. 3

mRNA expression analyses. Relative mRNA expression of KLLN (A), PTEN (B) and PTENP1 (C), determined by qPCR using 36B4 as a reference gene. Control individuals were compared to subgroups of PHTS patients according to the variant status of PTEN. Only significant differences are indicated (two tailed t-test; *p < 0.05; **p < 0.01; ***p < 0.001; **** p < 0.0001). Each dot represents the mean value of the expression of the gene under study for each patient (assessed in triplicate). The mean value of each group ± SEM is indicated