Exploring the Role of IDH1 Somatic Mutation in Tumorigenesis: A Review of Case Reports and Case Series Data from Nucleati Germline Cancer Evidence Base

By Nucleati Team
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Introduction:

Isocitrate dehydrogenase 1 (IDH1) is an enzyme that plays a crucial role in cellular metabolism by catalyzing the conversion of isocitrate to alpha-ketoglutarate (α-KG) in the citric acid cycle. Mutations in IDH1 have been identified as drivers of tumorigenesis in a variety of cancers, including gliomas, acute myeloid leukemia (AML), and chondrosarcomas. The discovery of IDH1 mutations has led to the development of targeted therapies and has significantly improved the understanding of the molecular mechanisms involved in the development of cancer. In this article, we will review the case reports and case series data on IDH1 somatic mutations from the Nucleati Germline Cancer Evidence Base and discuss their role in tumorigenesis.
Somatic mutations in isocitrate dehydrogenase 1 (IDH1) have been increasingly recognized as a critical factor in tumorigenesis across various types of cancer. Recent advancements in molecular genetics have enabled the identification and characterization of IDH1 mutations in different tumors, shedding light on their potential role in tumor initiation and progression. This article compiles and summarizes the findings of various case reports and case series studies that describe the presence and impact of IDH1 mutations in different types of tumors. By examining the general trends and commonalities among these studies, we aim to provide a comprehensive understanding of the role of IDH1 mutations in tumorigenesis and their implications for diagnosis and treatment.

Case Reports

PMID: 21552114 [S]

  • Patient/Family: 4 men and 3 women, ages 31 to 57, with anaplastic oligodendrogliomas and oligoastrocytomas. IDH1:R132H mutant protein was detected in 3 cases, and an IDH mutation (R132S) was identified in another case.
  • Gene/Variation: IDH1 mutations, R132H and R132S.
  • Clinical Characteristics: Oligodendroglial tumors with desmoplasia were rare and had 1p19q codeletion and IDH1 mutations. Recurrence/progression was common. One patient died.

PMID: 26123062 [G]

  • Patient/Family: A Chinese patient with Maffucci syndrome and her mother.
  • Gene/Variation: No pathogenic mutations found in IDH1 and IDH2 genes, 2 genes related to tumorigenesis found in chromosome microarray analysis.
  • Clinical Characteristics: First molecular genetic analysis report on a Chinese patient with Maffucci syndrome. Relationship between CHEK2, EP300 and Maffucci syndrome needs to be further explored.

PMID: 21552114 [S]

  • Patient/Family: Seven patients with oligodendroglial tumors, aged 31 to 57 years, four men, and three women, were studied.
  • Gene/Variation: Most cases showed 1p19q codeletion and IDH1 mutations.
  • Clinical Characteristics: Oligodendroglial tumors with prominent desmoplasia are rare, and most cases behave as expected for anaplastic oligodendroglial tumors.

PMID: 28544751 [S]

  • Patient/Family: A 15-year-old female with Maffucci syndrome had B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Hemangioma and leukemic cells had an IDH1 mutation. 
  • Gene/Variation: IDH1 mutation found in leukemic cells and hemangioma. 
  • Clinical Characteristics: Patients with Maffucci syndrome may be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation. 

PMID: 28720665 [S]

  • Patient/Family: Multiple pheochromocytomas and paragangliomas in eleven patients studied. 
  • Gene/Variation: IDH1, GOT2, and SDHC mutations found in some tumors. 
  • Clinical Characteristics: Mutations in Krebs cycle genes are relevant to the development of PCC and PGL, and other metabolic enzymes may play a role in metabolite exchange between mitochondria and cytosol. 

PMID: 26508204 [G/S]

  • Patient/Family: A 7-year-old girl with Maffucci syndrome developed acute myeloid leukemia (AML) with cup-like nuclear invagination. 
  • Gene/Variation: The patient had an insertion frameshift c.863_864insTCTG (p.W288fs) in the nucleophosmin (NPM1) gene and a missense mutation c.392_395GTCG>CTCT (p.G131_R132>AL) in the IDH1 gene in both leukemic cells and hemangioma. 
  • Clinical Characteristics: Multiple somatic mutations of IDH1 and NPM1 genes in hemangioblasts are related to the development of cup-like AML associated with Maffucci syndrome. 

PMID: 26473790

  • Patient/Family: A patient with Maffucci syndrome presented with intracranial tumors of the skull base and suprasellar region. 
  • Gene/Variation: The patient had identical IDH1 mutations (c.394C > T) in both chondrosarcoma and pituitary adenoma. 
  • Clinical Characteristics: The first genetic evidence for the inclusion of pituitary adenomas among tumors characterizing Maffucci syndrome, appropriate to monitor for the development of pituitary pathology and neuroendocrine dysfunction. 

PMID: 29846902 [S]

  • Patient/Family: A paraganglioma with concurrent IDH1 and ATRX mutations was identified in one patient. 
  • Gene/Variation: The paraganglioma had a somatic IDH1 mutation (c.394C>T, p.R132C) and a concurrent somatic ATRX splicing mutation (c.4318-2A>G). 
  • Clinical Characteristics: A somatic R132C mutation of IDH1 might play a role in a small subset of sporadic PPGLs.

PMID: 29138945 [S]

  • Patient/Family: Four patients with neurofibromatosis 1 (NF1) and glioblastoma were analyzed. 
  • Gene/Variation: None of the NF1 glioblastomas harbored IDH1, BRAF, or TERT gene mutations. 
  • Clinical Characteristics: NF1 glioblastoma is a unique subset of glioblastoma with a relatively favorable survival.

PMID: 29224049 [S]

  • Patient/Family: A 32-year-old man with a long history of enchondromatosis developed a left frontal tumor, and his enchondroma and glioma-matched pair specimens had a common IDH1 c.395G>A (R132H) mutation.
  • Gene/Variation: IDH1 c.395G>A (R132H) mutation.
  • Clinical Characteristics: The patient had a low-grade glioma with IDH1 mutation and 1p/19q codeletion, leading to a definitive diagnosis of oligodendroglioma. The first case of molecularly confirmed oligodendroglioma associated with enchondromatosis.

PMID: 31475115 [S]

  • Patient/Family: A 5-year-old patient with Shwachman-Diamond syndrome (SDS) developed AML and serial bone marrow monitoring revealed no cytogenetic anomalies nor signs of clonal hematopoiesis.
  • Gene/Variation: IDH1 c.394C>T/p.Arg132Cys mutation.
  • Clinical Characteristics: The patient had SDS-associated AML, and IDH1 mutation was likely associated with variable outcomes, and additional mechanisms such as TP53 mutations or monosomy 7 were absent.

PMID: 32612806 [S]

  • Patient/Family: An anaplastic ependymoma was analyzed for genomic changes by NGS.
  • Gene/Variation: IDH1 c.395G>A, PIK3CA c.1173A>G, KDR c.1416A>T, and TP53 c.215C>G mutations were identified.
  • Clinical Characteristics: The tumor had one deleterious missense IDH1 mutation and one novel synonymous mutation. Many of the variants reported here have not been detected in ependymal tumors by NGS analysis previously.

PMID: 33292606

  • Patient/Family: A 58-year-old male patient with refractory AML and persistence of RUNX1, IDH1 and DNMT3A mutations. Leukemia cutis ensued with NRAS mutations in addition to IDH1 and DNMT3A mutations.
  • Gene/Variation: Refractory AML presented with RUNX1, IDH1, and DNMT3A mutations, and leukemia cutis exhibited NRAS mutations in addition to IDH1 and DNMT3A mutations.
  • Clinical Characteristics: Presentation of leukemia cutis with simultaneous mutations of IDH1, DNMT3A, and NRAS in AML patients might act as a resistant niche to avoid the toxicity of multiple drugs including venetoclax plus 5-azacytidine (VA).

PMID: 35152189 [S]

  • Patient/Family: Not applicable
  • Gene/Variation: Missense mutation in c.395G>A in exon 4 of the IDH1 gene, and a missense mutation in c.215C>G in exon 4 of the TP53 gene were found in a primary intracranial myxopapillary ependymomas tumor.
  • Clinical Characteristics: The frequency of IDH1 variant was low, and the frequencies of other variants were high in the tumor. The reported variants have not been detected in myxopapillary grade I ependymoma tumor by NGS analysis previously, and are reported for the first time in this case.

PMID: 34720940 [S]

  • Patient/Family: A 35-year-old woman with Maffucci syndrome and IDH1 mutation.
  • Gene/Variation: IDH1 mutation at c.394C>T (R132C).
  • Clinical Characteristics: Maffucci syndrome complicated by intrahepatic cholangiocarcinoma with dissemination and metastases.

PMID: 33495182 [S]

  • Patient/Family: A 72-year-old Caucasian woman with chondrosarcoma of the hand and sclerosing pneumocytomas.
  • Gene/Variation: IDH1 mutation.
  • Clinical Characteristics: Sclerosing pneumocytomas; differentiation from lung cancer is a diagnostic challenge.

PMID: 34588213 [S]

  • Patient/Family: An adult male with multiple soft palpable lesions on the right upper limb.
  • Gene/Variation: Somatic mosaic c.394C > T (p.R132C) variant in exon 5 of IDH1.
  • Clinical Characteristics: Maffucci syndrome with a recognized risk of malignant transformation.

PMID: 35765075 [S]

  • Patient/Family: A 45-year-old man with Maffucci syndrome (MS) diagnosed with giant chondrosarcoma in the left ankle. 
  • Gene/Variation: IDH1 R132C mutation was identified in the chondrosarcoma lesion but not in the blood DNA.
  • Clinical Characteristics: The case showed MS complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation, which requires careful monitoring for the development of MS pathology and other concomitant lesions.

PMID: 35991838 [S]

  • Patient/Family: Five patients with IDH1 mutations associated with brainstem gliomas, including four cases of IDH1 R132H mutations and one case of R132G mutation.
  • Gene/Variation: IDH1 mutations were identified in the brainstem gliomas, along with pathogenic variants of TP53 and some genes related to a worse prognosis, such as CDK4/6 amplification.
  • Clinical Characteristics: The specific characteristics of IDH-mutant brainstem gliomas should be considered in diagnostic workflows to make therapeutic regimens and improve the prognosis.

Case series/multi patients studies

PMID: 19340432 [S]

  • Cohort: Three families with Li-Fraumeni syndrome and five astrocytomas with TP53 germline mutation. 
  • Setup: IDH1 mutations in astrocytomas were assessed. 
  • Outcomes: All IDH1 mutations were R132C, which is selective occurrence may reflect differences in genetic events. 

PMID: 20946881 [S]

  • Cohort: 456 Chinese patients with hematological malignancies and disorders. 
  • Setup: IDH1 and IDH2 mutations were screened. 
  • Outcomes: IDH1 and IDH2 missense mutations were observed in patients with AML. Frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. 

PMID: 19915015 [S]

  • Cohort: 365 pheochromocytomas and paragangliomas. 
  • Setup: Codons 132 and 172 were screened for IDH1 and IDH2 mutations. 
  • Outcomes: IDH mutations are very rare in paragangliomas and pheochromocytomas and do not play a significant role in oncogenic HIF activation.

PMID: 20130071 [S]

  • Cohort: 104 pheochromocytomas and paragangliomas 
  • Setup: Investigated IDH1, IDH2, and SDHAF2 genes in tumors with a pseudohypoxic expression profile
  • Outcomes: No mutations found in IDH1, IDH2, or SDHAF2 in any of the tumors. Conserved residues of these genes are not frequently mutated in these tumors.

PMID: 20068184 [S]

  • Cohort: 63 patients with AML secondary to preexisting MPN (sAML)
  • Setup: Investigated TET2, ASXL1, IDH1, and JAK2 mutations in sAML
  • Outcomes: Mutations in TET2, ASXL1, and IDH1 are common in sAML derived from preexisting MPN. TET2 mutations frequently acquired at leukemic transformation. Mutational order of events in MPN and sAML varies in different patients. 

PMID: 20376086 [S]

  • Cohort: 531 AML patients, 257 pediatric and 274 adult
  • Setup: Tested IDH1 mutations in patients with AML 
  • Outcomes: No IDH1(R132) mutations were found in pediatric patients, but found in 12 of 274 adult patients. IDH1(R132) mutations occurred commonly in patients with normal karyotype, FLT3/ITD, and NPMc mutations. No significant difference in survival or relapse-free survival between groups.

PMID: 22588899 [S]

  • Cohort: The study analyzed a set of primary brain tumors, including 18 oligodendrogliomas, 42 oligoastrocytomas, 10 astrocytomas, 16 glioblastomas, and 12 medulloblastomas.
  • Setup: The study analyzed CIC and FUBP1 mutations in brain tumors with allelic losses on 19q and 1p. CIC and FUBP1 mutations exclusively occurred in presence of IDH1 or IDH2 mutations.
  • Outcomes: The study confirms CIC and FUBP1 mutations in oligodendrogliomas and demonstrates their presence in oligoastrocytomas, clustering with IDH1/2 mutations.

PMID: 22494415 [S]

  • Cohort: The study investigated 195 Chinese patients with de novo AML.
  • Setup: The study screened mutations in IDH1, IDH2, JAK2 V617F, NPM1, FLT3, and KIT genes.
  • Outcomes: IDH mutations occurred in 15.89% of Chinese AML cases, with IDH2 R140Q being the most frequent. IDH2 mutation was strongly associated with NPM1 mutations and a trend with FLT3-internal-tandem duplication.

PMID: 23619563 [S]

  • Cohort: 879 primary myelofibrosis (PMF) patients, 483 European and 396 Mayo Clinic patients.
  • Setup: Somatic mutations were studied, including ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL, and JAK2.
  • Outcomes: ASXL1, SRSF2, and EZH2 mutations inter-independently predicted shortened survival, with only ASXL1 mutations remaining significant in the context of the International Prognostic Scoring System (IPSS). IDH1/2, SRSF2, and ASXL1 mutations negatively affected leukemia-free survival. Mutational profiling can identify PMF patients at risk for premature death or leukemic transformation.

PMID: 25640387 [S]

  • Cohort: 45 normal karyotype acute myeloid leukemia (AML) patients.
  • Setup: Mutations in DNMT3A (R882), IDH1 (R132), and IDH2 (R140 and R172) genes were analyzed.
  • Outcomes: DNMT3A and IDH mutations were observed in 13.3% and 15.4% of patients, respectively, with both mutations observed in two cases. DNMT3A and IDH mutations were significantly associated with NPM1, with trends towards higher coexistence with FLT3 mutations observed.

PMID: 27591990 [G]

  • Cohort: 104 familial cases with hematological malignancies and cosegregated solid tumors from Tunisian and French populations
  • Setup: IDH1 and IDH2 genes were targeted to determine whether germline isocitrate dehydrogenase genes mutations are involved. One IDH1 variant and three IDH2 variants were found, one of which was assigned to the worst outcome in several studies. 
  • Outcomes: IDH2 might be considerably involved in familial hematological malignancies since we reported a potential damaging effect of one of its variants.

PMID: 29077933 [S]

  • Cohort: 4 patients with multicentric lower-grade gliomas 
  • Setup: Clinical features, histology, and immunohistochemistry were integrated for phylogenetic analysis of the lesions using exome sequencing to study the heterogeneity among distinct tumor foci in a single patient. 
  • Outcomes: Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can significantly alter diagnosis and management. Somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation.

PMID: 29504908 [S]

  • Cohort: The study investigated 52 patients with carotid body tumor (CBT) to identify driver mutations.
  • Setup: Exome analysis revealed 21 genes with potential driver mutations (PDMs), including ARNT, BAP1, IDH1, TP53, and SDHB.
  • Outcomes: The study identified the average mutation load for CBTs and revealed the frequency and co-occurrence of PDMs. CBT formation was probably caused by the cumulative effect of several not highly pathogenic mutations.

PMID: 29858379

  • Cohort: The study reported two patients, a mother and her daughter, with familial brain tumors.
  • Setup: Exome sequencing revealed a germline missense mutation in TP53 and ATRX genes in both cases, and a somatic copy-neutral LOH in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors.
  • Outcomes: The study described the tumor development in a predisposed genetic background and showed that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development in the mother.

PMID: 29727824 [S] 

  • Cohort: The study investigated 289 Chinese patients with newly diagnosed de novo acute myeloid leukemia (AML).
  • Setup: NPM1 and CEBPA, IDH1 and IDH2 hotspot mutations, and WT1 mutations in exons 7 and 9 were analyzed by PCR.
  • Outcomes: The study found a higher frequency of CEBPA mutations, similar frequency of IDH2 mutations, and lower frequencies of NPM1, IDH1, and WT1 mutations compared to patients of predominately European descent, indicating different topographies of AML-associated mutations in different populations.

Summary and Conclusions:

In summary, IDH1 somatic mutations have been identified in various types of tumors, including oligodendrogliomas, AML, and paragangliomas. These mutations have been shown to play a crucial role in tumorigenesis, and the knowledge of these mutations can aid in the diagnosis, prognosis, and treatment of these tumors.
The Nucleati Germline Cancer Evidence Base has provided a valuable source of data for the case reports and case series analyzed in this blog article. Through this database, researchers and clinicians have access to a wealth of information about genetic mutations associated with various types of cancer.
In conclusion, the study of IDH1 somatic mutations has revealed important insights into the development and progression of several types of cancer. With continued research, these findings may lead to more personalized and effective treatment options for patients with these tumors. The Nucleati Germline Cancer Evidence Base provides a powerful tool for researchers and clinicians to continue advancing our understanding of the role of genetics in cancer.

References