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<p>Well-differentiated fetal lung adenocarcinoma (WDFLAC) is a rare pulmonary carcinoma characterized by its resemblance to fetal lung. It is thought to be caused by somatic pathogenic variants (PVs) in the genes <i>CTNNB1</i> or <i>APC</i>, which lead to the nuclear accumulation of beta(β)-catenin and down-stream activation of key oncogenes. Recent studies, however, have shown that germline and/or somatic PVs in DICER1 are also implicated in the etiology of lung tumors with fetal-type morphologies. Here, we report the second case of WDFLAC in a male non-smoker with familial adenomatous polyposis (FAP), and the first case with confirmed inactivating PVs in both <i>APC</i> and <i>DICER1</i>. A review of the literature also showed that out of the 17 WDFLAC cases for which sequencing of <i>DICER1, CTNNB1</i> and/or <i>APC</i> was performed, 13 had PVs in <i>DICER1</i> and either <i>CTNNB1</i> or <i>APC</i>, with one patient having all three genes mutated. Taken together, this suggests that the development of WDFLAC may be the summative effect of WNT and DICER1 dysfunction. It may thus be beneficial to test for <i>DICER1</i> variants in diagnostically challenging cases and, if a germline <i>DICER1</i> PV is found, additional screening for DICER1-associated tumors could be pursued.</p>

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Somatic DICER1 pathogenic variants detected in a well-differentiated fetal lung adenocarcinoma diagnosed in a man with familial adenomatous polyposis

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  • 发表日期：

    2025年11月6日

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  • Afrida Ahmed,
  • Paul S. Thorner,
  • Anne-Laure Chong,
  • Naciba Benlimame,
  • David Szlachtycz,
  • George Chong,
  • Sophie Camilleri-Broët,
  • William D. Foulkes

摘要

Well-differentiated fetal lung adenocarcinoma (WDFLAC) is a rare pulmonary carcinoma characterized by its resemblance to fetal lung. It is thought to be caused by somatic pathogenic variants (PVs) in the genes CTNNB1 or APC, which lead to the nuclear accumulation of beta(β)-catenin and down-stream activation of key oncogenes. Recent studies, however, have shown that germline and/or somatic PVs in DICER1 are also implicated in the etiology of lung tumors with fetal-type morphologies. Here, we report the second case of WDFLAC in a male non-smoker with familial adenomatous polyposis (FAP), and the first case with confirmed inactivating PVs in both APC and DICER1. A review of the literature also showed that out of the 17 WDFLAC cases for which sequencing of DICER1, CTNNB1 and/or APC was performed, 13 had PVs in DICER1 and either CTNNB1 or APC, with one patient having all three genes mutated. Taken together, this suggests that the development of WDFLAC may be the summative effect of WNT and DICER1 dysfunction. It may thus be beneficial to test for DICER1 variants in diagnostically challenging cases and, if a germline DICER1 PV is found, additional screening for DICER1-associated tumors could be pursued.