CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer

Davide Viotto, Francesca Russo, Ilaria Anania, Ilenia Segatto, Gian Luca Rampioni Vinciguerra, Alessandra Dall'Acqua, Riccardo Bomben, Tiziana Perin, Martina Cusan, Monica Schiappacassi, Lorenzo Gerratana, Sara D'Andrea, Francesca Citron, Filippo Vit, Lorena Musco, Maria Chiara Mattevi, Giorgia Mungo, Milena S. Nicoloso, Maura Sonego, Samuele MassarutRoberto Sorio, Luigi Barzan, Giovanni Franchin, Giorgio Giorda, Emilio Lucia, Sandro Sulfaro, Vittorio Giacomarra, Jerry Polesel, Federica Toffolutti, Vincenzo Canzonieri, Fabio Puglisi, Valter Gattei, Andrea Vecchione, Barbara Belletti, Gustavo Baldassarre

Research output: Contribution to journalArticlepeer-review


The CDKN1B gene, encoding for the CDK inhibitor p27kip1, is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor-positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell-free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C-terminal domain. Using a gene-editing approach in a luminal breast cancer cell line, MCF-7, we observed that the expression of p27kip1 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C-terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer.

Original languageEnglish
Pages (from-to)234-245
Number of pages12
JournalJournal of Pathology
Issue number2
Publication statusPublished - Feb 2021


  • breast cancer
  • CDKN1B
  • copy number variation, CNV
  • head and neck squamous cell carcinoma
  • liquid biopsy
  • mutation
  • ovarian cancer
  • p27
  • young breast cancer patients

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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