57
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Colon adenocarcinoma and Birt–Hogg–Dubé syndrome in a young patient: case report and exploration of pathologic implications

      research-article
      a , b , c , b , d
      Cancer Biology & Therapy
      Taylor & Francis
      Birt–Hogg–Dubé syndrome, colorectal cancer, folliculin gene, FLCN mutation, Wnt signaling

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene ( FLCN) that result in the functional loss of the tumor suppressor folliculin. It is classically associated with cutaneous hamartomas, pulmonary cysts with spontaneous pneumothorax, and various renal cancers. In this case, we present a patient initially diagnosed with chromophobe renal cell carcinoma and subsequently found to have colorectal cancer (CRC). The presence of two separate malignancies in a young patient with a strong family history of CRC (father and paternal grandfather) led to genetic testing, which revealed an FLCN c.1177–5_1177-3del mutation, and a diagnosis of BHD was made. Out of the more than 300 known unique mutations of the FLCN coding region, the c.1285dupC mutation on exon 11 has been the only one convincingly associated with CRC thus far. While larger cohort studies are needed to further clarify this association, we present the first patient with CRC to our knowledge with an FLCN c.1177–5_1177-3del mutation and loss of heterozygosity implicating it as an initiating factor in tumorigenesis. We further explore the studies supporting and refuting the connection between BHD and CRC and highlight the molecular signaling pathways that may play a role in pathogenesis.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: not found

          Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.

          Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.
            • Record: found
            • Abstract: found
            • Article: not found

            Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

            In a sibship of nine, six members had hereditary medullary carcinoma of the thyroid. Two of those with thyroid neoplasms and two without had numerous small papular skin lesions. These proved to be a type of pilar tumor that we named fibrofolliculoma. Further investigation of the total kindred of 70 showed no other evidence of thyroid neoplasm. Skin tumors only appeared after the age of 25 years. Fifteen of 37 members older than the age of 25 years exhibited the typical skin lesions. Obviously, the original sibship was the repository of two dominantly inherited traits. The fibrofolliculoma is characterized by abnormal hair follicles with epithelial strands extending out from the infundibulum of the hair follicle into a hyperplastic mantle of specialized firbrous tissue. Associated skin lesions in this kindred were trichodiscomas and acrochordons.
              • Record: found
              • Abstract: found
              • Article: not found

              Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.

              Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.

                Author and article information

                Journal
                Cancer Biol Ther
                Cancer Biol Ther
                Cancer Biology & Therapy
                Taylor & Francis
                1538-4047
                1555-8576
                1 March 2023
                2023
                1 March 2023
                : 24
                : 1
                : 2184153
                Affiliations
                [a ]Department of Internal Medicine, Thomas Jefferson University; , Philadelphia, PA, USA
                [b ]Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University; , Philadelphia, PA, USA
                [c ]Guardant Health Inc; , Redwood City, CA, USA
                [d ]Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University; , Philadelphia, PA, USA
                Author notes
                CONTACT Babar Bashir babar.bashir@ 123456jefferson.edu Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1025 Walnut Street, Suite 700, Philadelphia, PA 19017
                [*]

                Both authors contributed equally to the manuscript and share first co-authorship.

                Author information
                https://orcid.org/0000-0001-5329-9614
                https://orcid.org/0000-0001-8051-8800
                https://orcid.org/0000-0002-8366-5352
                https://orcid.org/0000-0002-6843-1179
                Article
                2184153
                10.1080/15384047.2023.2184153
                9988342
                36859772
                7ca0d155-2db2-4acb-b4fe-c2c9de7359ef
                © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 4, References: 26, Pages: 1
                Categories
                Research Article
                Research Paper

                Oncology & Radiotherapy
                birt–hogg–dubé syndrome,colorectal cancer,folliculin gene,flcn mutation,wnt signaling

                Comments

                Comment on this article

                Related Documents Log