Intratumoral heterogeneity of FLCN somatic mutations in gastric and colorectal cancers
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LETTER TO THE EDITOR
Intratumoral heterogeneity of FLCN somatic mutations in gastric and colorectal cancers Hyun Ji Son 1 & Eun Ji Choi 1 & Nam Jin Yoo 1 & Sug Hyung Lee 1 Received: 22 October 2019 / Accepted: 24 October 2019 # Arányi Lajos Foundation 2019
Dear Editor, FLCN gene encoding folliculin protein is a cytoplasmic guanine exchange factor associated with Birt-Hogg-Dubé (BHD) syndrome, the clinical manifestations of which include multiple tumors and pulmonary cysts [1]. Folliculin interacts with AMP-activated protein kinase (AMPK) and regulates energy metabolism in cells [1]. Activation of AMPK-related mTOR pathway may be responsible for tissue lesions [1]. In BHD syndrome, skin and kidney tumors are common, but colon tumors have also been reported in some individuals with BHD [2]. Frameshift mutations in the C8 mononucleotide repeat in exon 8 are the most common inactivating mutation in BHD individuals [1, 2]. The same frameshift mutations of FNCL are detected in sporadic colorectal cancer (CRC) with high microsatellite instability (MSI-H) (16% (5/32) of one study, 0% (0/5) of the other study) [3, 4]. Together, FLCN is considered a tumor suppressor gene (TSG). Approximately 10–20% of gastric (GC) and CRC are MSI-H cancers that exhibit genetic hypermutability caused by impaired DNA mismatch repair [5]. Many TSGs harbor frameshift mutations at monocleotide repeats in MSI-H cancers, which results in suppression of TSG and promotes cancer development [6]. In the present study, we analyzed the C8 repeat in FLCN in sporadic GC and CRC by polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis. We used 32 sporadic GCs with MSI-H, 45 GCs with microsatellite stable (MSS), 100 CRC with MSI-H and 45 CRCs with MSS. Also, we analyzed 16 cases of MSI-H CRCs with 4 to 7 regional fragments per CRC to detect intratumoral heterogeneity (ITH) of these mutations. In cancer tissues, malignant cells and normal cells were selectively procured by microdissection [6].
* Sug Hyung Lee [email protected] 1
Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, 137-701 Seoul, Korea
Radioisotope ([32P]dCTP) was incorporated into the PCR products, which were subsequently displayed in SSCP gels and analyzed with direct DNA sequencing [6]. In the analyses, we found frameshift mutations of the C8 of FLCN in 2 GCs and 24 CRCs (Table 1). The mutations were detected in cancers with MSI-H (GC: 2/32 (6.3%), CRC 24/100 (24%), GC + CRC: 26/132 (19.7%)), but not in those with MSS (0/90) (P
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