Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

Abstract

Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/ or the acquisition of additional genetic alterations.

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

“…Our analyses revealed that, consistent with primary PACs, recurrent PACs showed the canonical alterations affecting PRKD genes, including PRKD1 hotspot E710D mutations or a PRKD2 rearrangement. The maintenance of the highly recurrent/pathognomonic genetic alteration that characterises these tumours in the recurrences and after the acquisition of high-grade histological features is consistent with the observations made in other tumour types driven by pathognomonic genetic alterations, [41][42][43][44] and is consistent with the notion that these alterations constitute drivers of the disease. For instance, in the progression of adenoid cystic carcinomas to high-grade tumours, the MYB-NFIB fusion gene is maintained 41 ; likewise, in the progression of granulosa cell tumours, the FOXL2 C134W mutation is conserved.…”

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

“…In contrast to microglandular adenoses/atypical microglandular adenoses and breast acinic cell carcinomas, salivary gland-like tumors of the breast do not resemble conventional triple-negative breast cancers at the genetic level, harbor low levels of genetic instability with few copy number changes (12, 45) and do not harbor highly recurrent TP53 mutations (12). Although those lesions may also, albeit less frequently, progress to high-grade triple-negative breast cancers, there is evidence that those high-grade carcinomas also differ genetically from conventional triple-negative breast cancers (45, 46). Previous observations based on histologic and immunohistochemical analyses have suggested a potential association between microglandular adenosis and adenoid cystic carcinomas (47).…”

Adenoid cystic carcinoma of the breast

“…In this cancer, no mutations were observed occurring in triple-negative breast cancers such as TP53 and PIK3CA, whereas it shows somatic mutational heterogeneity affecting the functions of, among others, chromatin remodelling and cell adhesion [10].…”

“…Also, the frequency of local recurrences was lower after the application of radiotherapy. This is recommended in patients who have undergone conserving surgery, especially with the presence of positive margins [2,10,18].…”

“…Studies are being conducted in order to determine whether the transformation is possible of adenoid cystic carcinoma to triple-negative breast cancer -a cancer with much worse prognosis -through analogy to this type of cancer occurring in salivary glands, which is capable of transforming into highly aggressive cancers of various histologic types [10,11].…”