Genetic and immunohistochemical studies identify recurrent ACTB mutations and PTEN alterations in tubular adenomas of the breast.

AIMS: Tubular adenoma of the breast (TAB) is a rare and understudied neoplasm, initially thought to represent a fibroadenoma (FA) variant. Recently, it has been shown that TABs lack MED12 mutations indicating a distinct pathogenesis, and an association between multiple TABs and Cowden syndrome (CS) has been described. We sought to evaluate PTEN status in TABs with immunohistochemistry (IHC) and identify other potential molecular alterations.

METHODS AND

RESULTS

Forty-nine TABs from 43 patients (3 with CS, 40 without known CS) were retrieved. All patients were female, and ages ranged from 15 to 54 years old (median: 25). All TABs were well circumscribed and composed of closely packed, bilayered tubules with minimal intervening stroma. CS patients had multiple, bilateral TABs. PTEN IHC showed loss of expression in the luminal cells in TABs from all CS patients while the expression was retained in sporadic/non-CS TABs. Whole exome and/or Sanger sequencing was performed on 34 sporadic TABs and identified somatic missense mutations at codon 95 of the beta-actin gene, ACTB, in 19 cases (56%). No pathogenic MED12 mutations were identified in 29 TABs with next-generation sequencing results.

CONCLUSIONS

Overall, our findings highlight recurrent somatic ACTB mutations in more than half of sporadic TABs. CS-associated TABs but not sporadic TABs showed loss of PTEN expression. The presence of bilateral and/or multiple TABs should prompt PTEN IHC to rule out the possibility of CS.