Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.
Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.
The Netherlands Foundation for the Detection of Hereditary Tumors, Rijnsburgerweg 10, Poortgebouw Zuid, 2333 AA, Leiden, The Netherlands, m.nieuwenhuis@stoet.nl.
Marry H
MH
Nieuwenhuis
C Marleen
CM
Kets
Maureen
M
Murphy-Ryan
Helger G
HG
Yntema
D Gareth
DG
Evans
Chrystelle
C
Colas
Pal
P
Møller
Frederik J
FJ
Hes
Shirley V
SV
Hodgson
Maran J W
MJ
Olderode-Berends
Stefan
S
Aretz
Karl
K
Heinimann
Encarna B
EB
Gómez García
Fiona
F
Douglas
Allan
A
Spigelman
Susanne
S
Timshel
Noralane M
NM
Lindor
Hans F A
HF
Vasen
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013577:Syndrome; D013964:Thyroid Neoplasms / Q000235:genetics; D055815:Young Adult
D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human