Genetic analysis of microglandular adenosis and acinic cell carcinomas of the breast provides evidence for the existence of a low-grade triple-negative breast neoplasia family

Abstract

Acinic cell carcinoma is an indolent form of invasive breast cancer, whereas microglandular adenosis has been shown to be a neoplastic proliferation. Both entities display a triple-negative phenotype, and may give rise to and display somatic genomic alterations typical of high-grade triple-negative breast cancers. Here we report on a comparison of previously published data on eight carcinoma-associated microglandular adenosis and eight acinic cell carcinomas subjected to targeted massively parallel sequencing targeting all exons of 236 genes recurrently mutated in breast cancer and/or DNA repair-related. Somatic mutations, insertions/deletions and copy number alterations were detected using state-of-the-art bioinformatic algorithms. All cases were of triple-negative phenotype. A median of 4.5 (1–13) and 4.0 (1–7) non-synonymous somatic mutations per carcinoma-associated microglandular adenosis and acinic cell carcinoma were identified, respectively. TP53 was the sole highly recurrently mutated gene (75% in microglandular adenosis versus 88% in acinic cell carcinomas), and TP53 mutations were consistently coupled with loss of heterozygosity of the wild-type allele. Additional somatic mutations shared by both groups included those in BRCA1, PIK3CA and INPP4B. Recurrent (n=2) somatic mutations restricted to microglandular adenosis or acinic cell carcinomas included those affecting PTEN and MED12, or ERBB4, respectively. No significant differences in the repertoire of somatic mutations were detected between microglandular adenosis and acinic cell carcinomas, and between this group of lesions and 77 triple-negative carcinomas from The Cancer Genome Atlas. Microglandular adenosis and acinic cell carcinomas, however, were genetically distinct from estrogen receptor-positive and/or HER2-positive breast cancers from The Cancer Genome Atlas. Our findings support the contention that microglandular adenosis and acinic cell carcinoma are part of the same spectrum of lesions harboring frequent TP53 somatic mutations, and likely represent low-grade forms of triple-negative disease with no/minimal metastatic potential, of which a subset has the potential to progress to high-grade triple-negative breast cancer.

High rate of PIK3CA mutations but no TP53 mutations in low‐grade adenosquamous carcinoma of the breast

“…Recently Geyer et al . have reported on the existence of a ‘low‐grade triple‐negative breast neoplasia family’ featuring microglandular adenosis/atypical microglandular adenosis as non‐obligate precursors of TNBC, and acinic cell carcinomas as low‐grade forms of TNBC with the potential to transform into conventional high‐grade TNBCs.…”

“…have reported on the existence of a ‘low‐grade triple‐negative breast neoplasia family’ featuring microglandular adenosis/atypical microglandular adenosis as non‐obligate precursors of TNBC, and acinic cell carcinomas as low‐grade forms of TNBC with the potential to transform into conventional high‐grade TNBCs. Both microglandular adenosis/atypical microglandular adenosis associated with a carcinoma and acinic cell carcinomas have been shown to harbour TP53 mutations, and the acquisition of a TP53 mutation seems to represent the key event in the possible progression of microglandular adenosis/atypical microglandular adenosis to a carcinoma . In this respect, the lack of TP53 mutations and the presence of PIK3CA mutations in LGASC may suggest that these lesions follow a molecular evolutionary pathway that is distinct from that of conventional TNBC.…”

“…We observed that LGASCs seem to lack TP53 mutations and to harbour a relatively high frequency of PIK3CA mutations (52%), in stark contrast to high-grade spindle cell metaplastic carcinomas, which harbour both TP53 and PIK3CA mutations. Recently Geyer et al 28,29 have reported on the existence of a 'low-grade triple-negative breast neoplasia family' featuring microglandular adenosis/atypical microglandular adenosis as non-obligate precursors of TNBC, and acinic cell carcinomas as low-grade forms of TNBC with the potential to transform into conventional high-grade TNBCs. Both microglandular adenosis/atypical microglandular adenosis associated with a carcinoma and acinic cell carcinomas have been shown to harbour TP53 mutations, and the acquisition of a TP53 mutation seems to represent the key event in the possible progression of microglandular adenosis/ atypical microglandular adenosis to a carcinoma.…”

“…Both microglandular adenosis/atypical microglandular adenosis associated with a carcinoma and acinic cell carcinomas have been shown to harbour TP53 mutations, and the acquisition of a TP53 mutation seems to represent the key event in the possible progression of microglandular adenosis/ atypical microglandular adenosis to a carcinoma. 29 In this respect, the lack of TP53 mutations and the presence of PIK3CA mutations in LGASC may suggest that these lesions follow a molecular evolutionary pathway that is distinct from that of conventional TNBC. Interestingly, lesions such as papillomas, 30 RS/CSLs 31,32 and infiltrating epitheliosis 33 have also been shown to harbour PIK3CA mutations, and the causative role of PIK3CA mutations in these entities remains unclear.…”

Invasion in breast lesions: the role of the epithelial–stroma barrier

“…Cells of MGA show an immunophenotype that is different from hyperplastic epithelial cells in other breast lesions; they lack oestrogen receptor expression and show diffuse nuclear staining of S100 protein. Shared clonal driver mutations between uncommon cases with MGA and synchronous invasive carcinoma, suggestive of a precursor relationship, have been reported . Although atypia and carcinoma can arise from MGA, no metastasis has been reported in cases of pure MGA, which is the unequivocal hallmark and key clinical relevance of invasive disease.…”