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<p>Germline pathogenic variants (PV) in <i>CDKN2A</i> are characterized by an increased risk for melanoma, pancreatic cancer, nervous system tumors, and additional cancer types. We sought to define the tumor and clinical characteristics in a cohort of cancer patients with <i>CDKN2A</i> PV. Amongst 71,868 patients, 69 (0.1%) had a <i>CDKN2A</i> PV. Of these, 87.0% (<i>n</i> = 60), 7.2% (<i>n</i> = 5), and 5.8% (<i>n</i> = 4) had a PV impacting p16<sup>INK4A</sup>, p14<sup>ARF</sup>, or both p16<sup>INK4A</sup> and p14<sup>ARF</sup>, respectively. Biallelic inactivation of <i>CDKN2A</i> was observed in 33/47 (70.2%) of tumors assessed. Most tumors (28/38, 73.7%) in patients with p16<sup>INK4A</sup> PV demonstrated biallelic inactivation, including non-classic tumors such as lung cancer and osteosarcoma. Approximately half (5/9, 55.6%) of tumors in patients where p14<sup>ARF</sup> was impacted demonstrated biallelic inactivation, including peripheral nervous system tumors. This analysis supports a potential role of <i>CDKN2A</i> in the development of tumors beyond melanoma and pancreatic cancer and may have important implications for surveillance recommendations.</p>

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Paired tumor-normal sequencing provides insights into the CDKN2A-associated tumor spectrum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Kelsey E. Breen,
  • Nikita Mehta,
  • Vignesh Ravichandran,
  • Miika Mehine,
  • Chuan Gao,
  • Elise Fiala,
  • Semanti Mukherjee,
  • Ming Gao,
  • Kanika Arora,
  • Yelena Kemel,
  • Sydney Roth,
  • Angela G. Arnold,
  • Jennifer Kennedy,
  • Margaret Sheehan,
  • Faith Murphy,
  • Ryan Ptashkin,
  • Andrew Lin,
  • Michael Walsh,
  • Ozge Ceyhan-Birsoy,
  • William D. Tap,
  • Vineet Rolston,
  • Yonina R. Murciano-Goroff,
  • Alicia Latham,
  • Zsofia K. Stadler,
  • Kenneth Offit,
  • Diana Mandelker

摘要

Germline pathogenic variants (PV) in CDKN2A are characterized by an increased risk for melanoma, pancreatic cancer, nervous system tumors, and additional cancer types. We sought to define the tumor and clinical characteristics in a cohort of cancer patients with CDKN2A PV. Amongst 71,868 patients, 69 (0.1%) had a CDKN2A PV. Of these, 87.0% (n = 60), 7.2% (n = 5), and 5.8% (n = 4) had a PV impacting p16INK4A, p14ARF, or both p16INK4A and p14ARF, respectively. Biallelic inactivation of CDKN2A was observed in 33/47 (70.2%) of tumors assessed. Most tumors (28/38, 73.7%) in patients with p16INK4A PV demonstrated biallelic inactivation, including non-classic tumors such as lung cancer and osteosarcoma. Approximately half (5/9, 55.6%) of tumors in patients where p14ARF was impacted demonstrated biallelic inactivation, including peripheral nervous system tumors. This analysis supports a potential role of CDKN2A in the development of tumors beyond melanoma and pancreatic cancer and may have important implications for surveillance recommendations.