A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

Abstract

BackgroundAn 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.Case presentationWe 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.ConclusionThis 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.

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes

“…The major diagnostic criteria for PHTS include malignancies of the breast, thyroid and endometrium in addition to benign hamartomas, skin lesions and macrocephaly. 12 However, the symptoms associated with PTEN mutations are diverse and in some cases, germline mutations have been identified in adult patients only upon presentation with malignancy 13 14 and in patients with macrocephaly, autism and/or learning disability without further symptoms. 5 15 A series of clinical and laboratory based studies have presented evidence that mutational functional diversity and genetic background may each contribute to the phenotypical diversity observed in patients carrying PTEN mutations.…”

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To Dna Mutations

“…Women with mutations in PTEN have a BC risk in the range of 70-85% 75,76 , and in YWBC, the reported frequency of mutations in this gene represents < 1% 77 .…”

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

“…Frameshift variants accounted for 38.5% (5/13), splice-site variants for 23.1% (3/13), nonsense variants and deletions for 15.4% each (2/13), and missense variants for 7.7% (1/13). The only missense variant, c.71A>T; p.Asp24Val (patient IV), was demonstrated to be deleterious by functional analyses ( 24 ). Regarding the deletions, one was intragenic and limited to exon 2 (patient V), while the other (patient II) encompassed the entire PTEN sequence and other genes, as previously described ( 25 ).…”