A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer.
BACKGROUND
An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.


METHODS
We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.


CONCLUSIONS
This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.
Laura Maria
LM
Pradella
Cecilia
C
Evangelisti
Claudia
C
Ligorio
Claudio
C
Ceccarelli
Iria
I
Neri
Roberta
R
Zuntini
Laura Benedetta
LB
Amato
Simona
S
Ferrari
Alberto Maria
AM
Martelli
Giuseppe
G
Gasparre
Department of Medical and Surgical Sciences, Unit of Medical Genetics, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. daniela.turchetti@unibo.it.
Daniela
D
Turchetti
D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006223:Hamartoma Syndrome, Multiple / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human