Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia

Engel, Nils W.; Schliffke, Simon; Schüller, Ulrich; Frenzel, Christian; Bokemeyer, Carsten; Kubisch, Christian; Lessel, Davor

doi:10.3389/fonc.2019.00420

Cited by 16 publications

(11 citation statements)

References 57 publications

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“…This study highlights the significance of recognizing hypomorphic variants in cases of adult-onset FA. Subtle clinical findings underscore why clinicians must have a low threshold for testing for FA in unusually young patients with SCC as highlighted here and in patients with other cancers including AML, breast cancer, liver, and cholangiocarcinoma ( Huck et al 2006 ; Stevens et al 2016 ; Engel et al 2019 ). Malignancy was a major cause of morbidity and mortality for these patients, and FA-specific treatment regimens need to be selected given the extreme hypersensitivity to chemotherapy.…”

Section: Discussionmentioning

confidence: 90%

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

Lach

Singh

Rickman

et al. 2020

Cold Spring Harb Mol Case Stud

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Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype–phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.

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Section: Discussionmentioning

confidence: 90%

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

Lach

Singh

Rickman

et al. 2020

Cold Spring Harb Mol Case Stud

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“…Identification of synthetic vulnerability against FA mutant cells can lead to new therapeutic options. Treatment of cancer in FA patients is very challenging because of the increased toxicity of alkylating agent-based systemic chemotherapy (80,81), and targeted approaches would be more especially desirable. Given that FA gene deficiencies are increasingly identified as somatic mutations (6), the genetic connection between the FA pathway and Pol ι offers a synthetic lethality target for the elimination of tumor cells with FA pathway deficiency.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress

Wang

Lenoir

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4. As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.

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“…Fanconi anemia (FA) is a rare syndrome caused by mutations in the FA family of proteins, leading to chromosome instability, bone marrow failure, and other pathologies, including cancer. 3,4 The FA protein family consists of 15 members that regulate cell cycle progression and DNA damage repair. 5 Several studies have investigated the role of FA proteins in the occurrence and development of cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway</p>

Zheng¹,

Li²

2020

OTT

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Purpose: Fanconi anemia complementation group I (FANCI) is a key protein in ribosome biogenesis and DNA repair. Here, we aimed to determine the clinical significance, prognostic value and biology functions of FANCI in lung adenocarcinoma (LUAD). Methods: The expression of FANCI in LUAD tissue and its relationship with patient outcomes were assessed using bioinformatics analysis, as well as quantitative reverse-transcription PCR (qRT-PCR) and Western blot analysis of LUAD tissue and adjacent normal lung tissue. The chisquared test and Cox regression analysis were used to analyze the clinical significance of FANCI expression. The biological effects of FANCI knockdown in human LUAD cell lines were investigated by analysis of proliferation, colony formation, cell cycle distribution, migration, and invasion in vitro, and monitoring of tumor xenograft growth in vivo. FANCI interactions with IMPDH2 and involvement in MEK/ERK/MMPs signaling were analyzed using coimmunoprecipitation assays, immunofluorescence microscopy, and Western blotting. Results: FANCI was identified as a hub gene for LUAD. FANCI expression was upregulated in LUAD tissues compared with normal lung tissues and was positively associated with lymphatic metastasis, distant metastasis, and poor outcome. FANCI was also an independent prognostic factor in LUAD patients. Knockdown of FANCI in LUAD cell lines decreased their proliferation, migration, invasion, and cell cycle progression in vitro, and decreased the growth of xenografts in mice. Direct binding of FANCI to IMPDH2 decreased IMPDH2 degradation, regulated activation of MEK/ERK/MMPs signaling. Overexpression of IMPDH2 reversed the inhibitory effects of FANCI knockdown. Conclusion: FANCI may act as an oncogene in LUAD by cooperating with IMPDH2 to promote cell proliferation via the MEK/ERK/MMPs pathway. These results identify FANCI as a potential prognostic biomarker and therapeutic target for LUAD.

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Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia

Cited by 16 publications

References 57 publications

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress

<p>FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway</p>

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