Histologic and genomic features of breast cancers with alterations affecting the SWI/SNF (SMARC) genes Journal Article

   


Authors: Schwartz, C. J.; Pareja, F.; da Silva, E. M.; Selenica, P.; Ross, D. S.; Weigelt, B.; Brogi, E.; Reis-Filho, J. S.; Wen, H. Y.
Article Title: Histologic and genomic features of breast cancers with alterations affecting the SWI/SNF (SMARC) genes
Abstract: The SWI/SNF family of proteins is a multisubunit ATPase complex frequently altered in human cancer. Inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCs) underpin a subset of tumors such as the malignant rhabdoid tumor and small cell carcinoma of the ovary, hypercalcemic type. Here, we investigated the genotypic and phenotypic characteristics of breast cancers harboring somatic genetic alterations affecting genes of the SMARC family. We analyzed a series of 6026 primary and metastatic breast cancers subjected to targeted-capture sequencing. SMARC core subunit (SMARCA4, SMARCB1, and SMARCA2) alterations were identified in <1% of all breast cancers, consisting of 27 primary and 30 recurrent/metastatic tumors. The majority of SMARC alterations were monoallelic mutations (47/57, 82%) and thus categorized into two groups: Class 1 alterations consisting of potentially pathogenic mutations and rearrangements and Class 2 alterations consisting of missense mutations and small in-frame deletions of unknown significance. Biallelic events in a SMARC gene were present in a minority of cases (10/57, 18%). Histologic patterns in the form of rhabdoid, composite rhabdoid, sarcomatoid or anaplastic features were observed in a subset of Class 1 primary and metastatic tumors (7/57, 12%). SMARC protein was preserved in nearly all tumors analyzed with immunohistochemistry (26/30, 87%). Four Class 1 tumors demonstrated altered SMARC protein expression in the form of loss (1/30, 3%) or mosaic pattern (3/30, 10%). Complete loss of SMARCA2 (BRM) was observed in a sole tumor with composite rhabdoid morphology, and biallelic hits in the SMARCA2 gene. The genomic landscape of both primary Class 1 and 2 breast cancers did not reveal any characteristic findings. In summary, SMARC alterations likely contribute to the biology of a rare subset of breast cancers in the form of biallelic or pathogenic alterations in SMARC, as evidenced by SMARC-deficient phenotype or altered expression of SMARC protein. © 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Keywords: immunohistochemistry; adult; controlled study; human tissue; aged; primary tumor; gene mutation; major clinical study; missense mutation; histopathology; cancer recurrence; breast cancer; gene expression; gene frequency; morphology; cancer genetics; metastatic breast cancer; genotype phenotype correlation; mosaicism; brm protein; brg1 protein; human; female; article; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1
Journal Title: Modern Pathology
Volume: 34
Issue: 10
ISSN: 0893-3952
Publisher: Nature Research  
Date Published: 2021-10-01
Start Page: 1850
End Page: 1859
Language: English
PMCID: PMC8448940
DOI: 10.1038/s41379-021-00837-3
PROVIDER: scopus
PUBMED: 34079072
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107282739&doi=10.1038%2fs41379-021-00837-3&partnerID=40&md5=3749769d2eef346300125e89bb62f8ef
Notes: Article -- Source: Scopus
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MSK Authors
  1. Hannah Yong Wen
    301 Wen
  2. Edi Brogi
    515 Brogi
  3. Dara Stacy Ross
    144 Ross
  4. Britta Weigelt
    632 Weigelt
  5. Jorge Sergio Reis-Filho
    639 Reis-Filho
  6. Fresia Gilda Pareja Zea
    216 Pareja Zea
  7. Edaise Maria Da Silva
    95 Da Silva
  8. Pier Selenica
    189 Selenica
  9. Christopher Schwartz
    20 Schwartz
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