Table 1.
Summary of cycle enzyme genetic alterations in cancer
| Gene | Genetic alterations | Tumor context | Consequence of alterations |
References |
|---|---|---|---|---|
| SDHA | c.91C>T c.1765C>T c.212G>A c.674C>T, c.818C>T c.341A>G c.367C>A c.441delG c.725_736del c.989_9990insTA c.1753C>T c.1865G>A c.1873C>T c.1886A>T |
Paragangliomas Pheochromocytomas |
Leads to reduction or loss of enzymatic activity of the SDH catalytic subunit and defective function of mitochondrial complex II | (Burnichon et al., 2010; Bardella et al., 2011; Korpershoek et al., 2011; Dwight et al., 2013; Evenepoel et al., 2015; Pillai et al., 2017) |
| c.2T>C c.91C>T c.113A>T c.160C>T c. 206C>T c.224G>A c.244A>T c.T273I c.457-3 457-1delCAG c.457-2 c457delCAG c.511C>T c.553C>T c.562C>T c.688delG c.767C>T c.778G>A c.800C>T c.818C>T c.985C>T c.1043-1055del c.1046 147delTG c.1151C>G c.1255G>A c.1334C>T c.1357G>A c.1361C>A c.1471G>T c.1534C>T c.1690G>A c.1765C>T c.1766G>A c.1794G>C c.1795-1G>T c.1873C>T c.1969G>A |
Gastrointestinal stromal tumors | (Pantaleo et al., 2011; Italiano et al., 2012; Belinsky et al., 2013a; Belinsky et al., 2013b; Miettinen et al., 2013; Oudijk et al., 2013; Miettinen and Lasota, 2014; Evenepoel et al., 2015; Jiang et al., 2015) | ||
| c.2T>C | Renal cell carcinoma | (Jiang et al., 2015) | ||
| SDHB | c.-1- ?_72+ ?del c.-1- ?_765+ ?del c.3G>A c.21delC c.49delA c.72+1G>A c.73_76delGCCT c.79C>A c.136C>G c.137G>A c.141G>A c.155delC c.166-170delCCTCA c.203G>A c.213C>T c.221insCCAG c.238A>G c.268C>T c.269G>A c.270C>G c.271G>A c.277T>C c.287-2A>G c.287- ?_540+ ?del c.291G>A c.293G>A c.299C>T c.300-4delCCTCA c.300T>C c.312insCACTGCA c.328C>T c.394T>C c.402C>T c.416T>C c.421-2A>G c.423+1G>A c.438G>A c.540G>A c.541-2A>G c.549_552delTACinsATACAG c.557G>A c.558-3C>G c.566G>A c.589C>T c.649C>T c.650G>T c.653G>A c.688C>T c.689G>A c.689G>T c.708T>C c.718_719delCT c.721G>A c.724C>G c.724C>A c.724C>T c.725G>A c.736A>T c.761C>T c.765+1G>A c.778G>C c.780delG c.847delTCTC c.859G>A c.881C>A c.889+1G>A |
Paraganglioma Pheochromocytoma |
Reduces SDH catalytic activity and causes defects in enzymatic activity in mitochondrial complex II | (Neumann et al., 2004, 2009; Bardella et al., 2011; Sjursen et al., 2013; Evenepoel et al., 2015; Bennedbaek et al., 2016) |
| c.32G>A c.88delC c.136C>T c.137G>A c.847-50delTCTC |
Renal cell carcinoma | (Vanharanta et al., 2004; Ricketts et al., 2008; Paik et al., 2014) | ||
| c.392delC | Thyroid carcinoma | (Zantour et al., 2004) | ||
| IVS1+1G>T c.17_dup26GTCG{dup26}GCCA c.17 42dup c.43+1C>T c.45_46insCC c.72+1G>T c.137G>A c.274T>A c.380T>G c.423+1G>C c.423+1G>A c.423+20T>A c.600G>T c.725G>A |
Gastrointestinal stromal tumors | (McWhinney et al., 2007; Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Miettinen and Lasota, 2014) | ||
| c.418G>T | Neuroblastoma | (Schimke et al., 2010) | ||
| c.587G>A | Pituitary carcinoma | (Tufton et al., 2017) | ||
| c.136C>T | T-cell acute leukemia | (Baysal, 2007) | ||
| SDHC | c.1A>G c.2T>A c.3G>A c.23dupA c.39C>A c.43C>T c.77 + 4760A>G c.78-2A>G c.78-19C>T c.112A>G c.126G>A c.140-5527C>A c.148C>T c.166A>T c.173T>C c.191_207del17 c.210C>G c.214C>T c.218insA c.224G>A c.242G>T c.242-5580C>A, c.212C>A c.253_255dupTTT c.397C>T c.405+1G>T c.439C>T c.496C>G IVS4+1G>A |
Paraganglioma Pheochromocytoma |
Leads to reduced SDH enzymatic activity and defective function in mitochondrial complex II | (Douwes Dekker et al., 2003; Mannelli et al., 2007; Peczkowska et al., 2008; Neumann et al., 2009; Bennedbaek et al., 2016; Pillai et al., 2017) |
| IVS5+1G>A c.1A>G c.6delT c.43C>T c.57delG c.224G>A c.301delT c.380A>G c.397C>T c.405+1G>A c.455G>C |
Gastrointestinal stromal tumors | (McWhinney et al., 2007; Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Miettinen and Lasota, 2014) | ||
| SDHD | c.2T>A c.3G>C c.14G>A c.33C>A c.33C>T c.34G>A c.36_37delTG c.49C>T c.50G>T c.52+2T>G c.53-2A>G c.53+2T>G c.55dupT c.64C>T c.106C>T c.112C>T c.118A>G c.120_ 127delCCCAGAAT c.129G>A c.149A>G c.168_169delTT c.169 + 5G>A, c.53-889G>A c.170-1G>T c.184_185insTC c.191_192delTC c.204-216del13bp c.206_218del13bp c.208A>G c.230T>G c.233_242del10bp c.242C>T c.252T>G c.274G>T c.276_278delCTA c.284T>C c.302T>C c.314+1G>C c.317delG c.325C>T c.334_337delACTG c.337_340delGACT c.341A>G c.341_342delAT c.361C>T c.367G>A c.370delG c.386_387insT c.408delT c.416T>C c.441delG c.443G>T IVS1+2T>G |
Paraganglioma Pheochromocytoma |
Reduces efficacy of SDH and impairs mitochondrial complex II activity | (Gimm et al., 2000; Taschner et al., 2001; Dannenberg et al., 2002; Douwes Dekker et al., 2003; Lee et al., 2003; Neumann et al., 2004; Simi et al., 2005; Galera-Ruiz et al., 2008; Neumann et al., 2009; Evenepoel et al., 2015; Bennedbaek et al., 2016; Pillai et al., 2017) |
| c.34G>A c.57delG c.352delG c.416T>C |
Gastrointestinal stromal tumors | (Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Oudijk et al., 2013; Miettinen and Lasota, 2014) | ||
| c.129G>A | Testicular seminoma | (Galera-Ruiz et al., 2008; Evenepoel et al., 2015) | ||
| SDHAF2 | c.68C>T c.139A>G c.232 G>A |
Paraganglioma Pheochromocytoma |
Leads to loss of flavination of SDH, reducing stability and activity of the enzyme complex | (Hao et al., 2009; Bayley et al., 2010; Pillai et al., 2017) |
| FH | p.Gln4X 1-bp del. In codon 17 p.Arg58X p.Asn64Thr p.Ala74Pro p.His137Arg p.Gln142Arg 2-bp del. In codon 181 Lys187Arg Lys del. In codon 187 Arg190His -15 splice site p.Gly239Val p.Arg300X 1-bp del. In codon 507 |
Multiple leiomyomatosis | Leads to loss of FH enzymatic activity and accumulation of fumarate in the cell | (Tomlinson et al., 2002) |
| c.1?_c.*100del c.1?_404+?del c.111insA c.127_128delGA c.138+1_138+10del10 c.147delT c.157G>T c.172C>T c.191A>C c.220G>C c.233del c.247_249+1delGAGGinsA c.250-2A>G c.266T>C c.298delA c.305C>G c.349A>G c.410A>G c.425A>G c.431C>T c.434A>G c.455T>C c.503T>C c.560A>G c.568C>T c.568delAC c.569G>A c.569G>T c.575A>G c.632A>G c.666delC c.698G>A c.780delGC c.782-788 7-bp del. c.806T>C c.808G>T c.810delA c.815T>C c.821C>T c.823C>T c.824G>A c.836T>A c.869G>A c.875T>C c.891T>A c.898C>T c.952C>T c.964A>G c.968G>A c.989A>G c.1002T>G 2-bp ins @1004 c.1020T>A c.1025C>A c.1028A>G c.1060G>A c.1083-1086delTGAA c.1108-2A>G c.1121-1123 del TAC c.1123delA c.1126T>C c.1138insA c.1144A>G c.1162delA c.1187A>C c.1189G>A c.1210G>T c.1234del c.1265A>G 8-bp dup @ 1300-1307 c.1339delG c.1349-1352delATGA c.1371G>A c.1431insAAA |
Hereditary leiomymatosis and renal cell carcinoma | (Toro et al., 2003; Wei et al., 2006; Pfaffenroth and Linehan, 2008; Gardie et al., 2011; Smit et al., 2011; Chen et al., 2014; Wong et al., 2014; Arenas Valencia et al., 2017) | ||
| c.220G>C c.426+1G>A c.988A>G c.994delA |
Type 2 papillary renal cell carcinoma | (Gardie et al., 2011) | ||
| c.1394G>A c.352A>C |
Leydig cell tumors (Carvajal-Carmona et al.) | (Carvajal-Carmona et al., 2006) | ||
| 435insAAA 691G>A |
Ovarian mucinous cystadenoma | (Ylisaukko-oja et al., 2006) | ||
| IDH1 | p.Arg100Gln p.Arg132His p.Arg132Cys p.Arg132Ser p.Arg132Leu p.Arg132Gly |
Gliomas/Glioblastomas | Increases affinity for NADPH/α-KG; reduces affinity for isocitrate; increases production of 2-HG | (Parsons et al., 2008; Dang et al., 2009; Yan et al., 2009; Pusch et al., 2011) |
| p.Arg132His p.Arg132Cys p.Arg132Ser p.Arg132Gly p.Arg132Leu |
Acute myeloid leukemia | (Mardis et al., 2009; Abbas et al., 2010; Bayley et al., 2010) | ||
| p.Arg132Cys p.Arg132Leu p.Arg132Gly p.Arg132Ser |
Myelodysplastic syndromes/ Myeloproliferative neoplasms | (Kosmider et al., 2010; Pardanani et al., 2010) | ||
| p.Arg132Cys p.Arg132His p.Arg132Leu p.Arg132Ser |
Chondrosarcoma | (Amary et al., 2011) | ||
| p.Arg132His p.Arg132Gly p.Arg132Ser p.Arg132Cys |
Acute lymphoblastic leukemia | (Kang et al., 2009; Zhang et al., 2012) | ||
| p.Gly70Asp p.Val71Ile p.Gly105Gly; p.Val1781Ile p.Gly123Arg p.Ile130Met p.His133Gln p.Ala134Asp |
Thyroid carcinoma | (Hemerly et al., 2010; Murugan et al., 2010) | ||
| p.Arg132Cys p.Arg132His |
Prostate carcinoma | (Kang et al., 2009; Ghiam et al., 2012) | ||
| IDH2 | p.Arg172Gly p.Arg172Met p.Arg172Lys |
Gliomas/Glioblastomas | Increases affinity for NADPH/α-KG; reduces affinity for isocitrate; increases production of 2-HG | (Yan et al., 2009) |
| p.Arg140Gln p.Arg172Lys p.Arg172Gln p.Arg172Thr p.Arg172Gly |
Angioimmunoblastic T-cell lymphoma | (Cairns et al., 2012; Lemonnier et al., 2016) | ||
| p.Arg140Gln p.Arg140Trp p.Arg172Lys p.Arg172Met |
Acute myeloid leukemia | (Abbas et al., 2010; Gross et al., 2010; Pardanani et al., 2010) | ||
| p.Arg140Gln p.Arg140Leu |
Myelodysplastic syndromes/ Myeloproliferative neoplasms | (Kosmider et al., 2010; Pardanani et al., 2010) | ||
| p.Arg172Ser | Chondrosarcoma | (Amary et al., 2011) |