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TABLE 2: Next Generation Sequencing Data on Non-Neoplastic Brain Tissue Glioblastoma is the most aggressive subtype of human brain tumors. Familial gliomas can be found in associaAon with certain hereditary disorders however isolated familial glioblastomas are exceedingly rare. Relevant hereditary factors have remained elusive. Understanding the geneAc alteraAon of familial glioblastoma may unfold some of the unknown mechanisAc pathways. MATERIALS AND METHODS Next Generation Sequencing of Familial Glioblastoma Edana Stroberg DO, Sanjib Mukherjee MD, PhD, Linden Morales, MS, Arundhati Rao, MD, PhD, Ekokobe Fonkem, DO Baylor Scott & White Healthcare-Texas A&M Health Science Center College of Medicine, Temple, Texas We report on next generaAon sequencing analysis of 3 cases of glioblastoma in a single family; a father and two children. The father was Introduction: Glioblastoma is the most aggressive subtype of human brain tumors. Familial gliomas can be diagnosed at the ge ohereditary f 38 and succumbed to hfamilial is disease in less than one found in association withacertain disorders however isolated glioblastomas are exceedingly rare. Relevant hereditary factors have remained elusive. Understanding the genetic alteration of familial year. The smay ame year, dunknown aughter was diagnosed with glioblastoma at glioblastoma unfold somehofis the mechanistic pathways. the a ge o f 6 a nd a lso d ied f rom h er d isease i n l ess t han o ne y ear. H is s on Material and Methods: We report on next generation sequencing analysis of 3 cases of glioblastoma in a single a fatherw and twoachildren. The father was at the ofa 38nd andis succumbed to his disease was dfamily; iagnosed ith glioblastoma at diagnosed the age of age 19 currently in less than one year. The same year, his daughter was diagnosed with glioblastoma at the age of 6 and also died being treated. There is year. no His other significant history. from her disease in less than one son was diagnosed withfamily a glioblastoma at the age of 19 and is currently being treated. There is no other significant family history. A B TABLEFather 2: Next Generation Sequencing Data on Non-Neoplastic Brain Tissue RESULTS INTRODUCTION Common Mutations Between Patients Microscopic secAons of the brain tumors from all three family members were reviewed. They each had similar histology including a pleomorphic astrocyAc phenotype, necrosis and microvascular hyperplasia (Figure 1). Samples from each tumor were submiMed for next generaAon sequencing to determine if common hotspot mutaAons were present. The common mutaAons are shown in Table 1 and Figure 2. The Assue submiMed from the father’s brain tumor demonstrated hotspot mutaAons in three genes; heterozygous mutaAons in PDGFRA and TP53 on chromosomes 4 and 17 respecAvely in addiAon to a homozygous mutaAon in HRAS on chromosome 11. The 6 year old daughter’s brain tumor showed homozygous mutaAons in PDGFRA, HRAS and SMARCB1 on chromosomes 4, 11 and 22 respecAvely. InteresAngly, the 19 year old son’s brain tumor showed heterozygous mutaAons in PDGFRA, and SMARCB1 on cfamily hromosomes 4, reviewed. 11 and They 22 each had Results: Microscopic sectionsH ofRAS the brain tumors from all three members were similar histologyN including a pleomorphic astrocytic phenotype, necrosis and microvascular hyperplasia (Figure and respecAvely. on-‐neoplasAc b rain A ssue f rom t he f ather a nd s on w ere a vailable 1). Samples from each tumor were submitted for next generation sequencing to determine if common hotspot mutations werein present. The common mutations are shown 1. The ttissue submitted from the father’s sequenced addiAon to their tumors. The in mTable utaAons he two individuals shared in brain tumor demonstrated hotspot mutations in three genes; heterozygous mutations in PDGFRA and TP53 on common are shown in Table . Non-‐neoplasAc rain Assue from the daughter chromosomes 4 and 17 respectively in 2 addition to a homozygousbmutation in HRAS on chromosome 11. Thew 6 as yearaold daughter’sThe brainfather tumor showed homozygous mutations in PDGFRA, HRAS and SMARCB1 on not vailable. a nd s on s hared h omozygous m utaAons i n F GFR3 a nd R ET chromosomes 4, 11 and 22 respectively. Interestingly, the 19 year old son’s brain tumor showed heterozygous mutations in PDGFRA,4HRAS on chromosomes 22 respectively.m Non-neoplastic on chromosomes and and 10 SMARCB1 respecAvely as well a4,s 11 a hand eterozygous utaAon in HRAS brain tissue from the father and son were available and sequenced in addition to their tumors. The mutations the on 1. common The father had homozygous mutaAons in from EGFR nd FLT3 n twochromosome individuals shared1in are shown in Table 2. Non-neoplastic brain tissue the a daughter wasonot available. The father son shared homozygous w mutations in FGFR3 on chromosomes 4 and 10 chromosomes 7 and and 13 respecAvely hile the son hand ad RET heterozygous mutaAons in respectively as well as a heterozygous mutation in HRAS on chromosome 11. The father had homozygous these genes. In and addiAon, the father 7sand howed a homozygous mhad ulAple nucleoAde mutations in EGFR FLT3 on chromosomes 13 respectively while the son heterozygous mutations in these genes. In addition, the father showed a homozygous multiple nucleotide pleomorphism in CSF1R on pleomorphism in theCSF1R on cahromosome 5 wnucleotide hile the son showed a heterozygous chromosome 5 while son showed heterozygous single polymorphism mutation in the same gene. Finally, the mutations from both neoplastic and non-neoplastic brain tissue were compared for m theutaAons father single nucleoAde polymorphism mutaAon in the same gene. Finally, the and son. The mutations common to both neoplastic and non-neoplastic brain tissue for each individual are from oth neoplasAc and non-‐neoplasAc brain Assue were compared for the father shownbin Table 3. and son. The mutaAons common to both neoplasAc and non-‐neoplasAc brain Assue for each individual are shown in Table 3. TABLE 1: Next Generation Sequencing Data on Neoplastic Brain Tissue Hotspot Mutations Father C D Chromosome chr4 chr11 chr17 Position 55152040 534242 7578211 Reference C A C Variant T G T Allele Call Heterozygous Homozygous Heterozygous Type SNP SNP SNP Allele Source Hotspot Hotspot Hotspot Gene ID PDGFRA HRAS TP53 Reference C A G Variant T G A Allele Call Homozygous Homozygous Homozygous Type SNP SNP SNP Allele Source Hotspot Hotspot Hotspot Gene ID PDGFRA HRAS SMARCB1 Reference C A G Variant T G A Allele Call Heterozygous Heterozygous Heterozygous Type SNP SNP SNP Allele Source Hotspot Hotspot Hotspot Gene ID PDGFRA HRAS SMARCB1 Daughter Chromosome chr4 chr11 chr22 Position 55152040 534242 24176287 Son Chromosome chr4 chr11 chr22 FIGURE 1. The brain tumors from all three family members showed similar histologic features. Hematoxylin FIGURE 1. The brain tumors rom all cells three family members howed similar and eosin (H&E)-stained section showingfneoplastic of astrocytic phenotype with ansatypical mitosis shown in circle (A). The neoplastic cells show prominent pleomorphism (B). There aresec>on areas of florid histologic features. Hematoxylin and eosin (H&E)-‐stained showing microvascular hyperplasia (C) and geographic necrosis (D) which confirm the diagnosis of glioblastoma. neoplas>c cells of astrocy>c phenotype with an atypical mitosis shown in circle (A). The neoplas>c cells show prominent pleomorphism (B). There are areas of florid microvascular hyperplasia (C) and geographic necrosis (D) which confirm the diagnosis of glioblastoma. Position 55152040 534242 24176287 !"#$%&'() SMARCB1 HRAS PDGFRA -"&%'() *+,) FIGURE 2. Venn diagram showing the rela>onship of hotspot muta>ons iden>fied in the neoplas>c brain >ssue from the family members. All three family members showed muta>ons in HRAS and PDGFRA while the son and daughter showed addi>onal muta>ons in SMARCB1. Chromosome Position chr4 1807894 Father chr5 Chromosome 149453049 Position chr7 55249063 chr4 1807894 chr10 43613843 chr5 149453049 chr11 534242 chr7 55249063 chr13 28610183 chr10 43613843 chr11 534242 Daughter chr13 28610183 Non-Neoplastic Brain Tissue Not Available Daughter Non-Neoplastic SonBrain Tissue Not Available Chromosome Position chr4 1807894 Son chr5 Chromosome 149433596 Position chr7 55249063 chr4 1807894 chr10 43613843 chr5 149433596 chr11 534242 chr7 55249063 chr13 28610183 chr10 43613843 chr11 534242 chr13 28610183 Common Between Reference Mutations Variant Allele Call Patients Type G G Reference G G A G A G A A A A Variant A T A G A G T G G Homozygous Heterozygous Allele Call Homozygous Homozygous Heterozygous Heterozygous Homozygous Homozygous Heterozygous Homozygous SNP SNP Type SNP SNP SNP SNP SNP SNP Allele Source Novel Novel Allele Source Novel Novel Novel Novel Novel Novel Reference G TG Reference G G TG A G A G A A Variant A GA Variant A T GA G A G T G G Allele Call Homozygous Homozygous Allele Call Heterozygous Homozygous Homozygous Heterozygous Heterozygous Homozygous Heterozygous Heterozygous Type SNP MNP Type SNP SNP MNP SNP SNP SNP SNP Allele Source Novel Novel Allele Source Novel Novel Novel Novel Novel Novel Gene ID FGFR3 CSF1R Gene ID EGFR FGFR3 RET CSF1R HRAS EGFR FLT3 RET HRAS FLT3 Gene ID FGFR3 CSF1R Gene ID EGFR FGFR3 RET CSF1R HRAS EGFR FLT3 RET HRAS FLT3 TABLE 3: Next Generation Sequencing Data Comparison Common Mutations in Neoplastic and Non-Neoplastic Brain Tissue for Each Patient TABLE Father 3: Next Generation Sequencing Data Comparison CommonPosition Mutations Chromosome chr7 55249063 Father chr4 Chromosome 1807894 Position chr13 28610183 chr7 55249063 chr11 534242 chr4 1807894 chr10 43613843 chr13 28610183 chr11 534242 Daughter chr10 43613843 Non-Neoplastic Brain Tissue Not Available to Compare Daughter Non-Neoplastic SonBrain Tissue Not AvailablePosition to Compare Chromosome chr5 112175770 Son chr5 Chromosome 149433596 Position chr7 55249063 chr5 112175770 chr4 1807894 chr5 149433596 chr13 28610183 chr7 55249063 chr11 534242 chr4 1807894 chr4 55141055 chr13 28610183 chr4 55152040 chr11 534242 chr3 178917005 chr4 55141055 chr10 43613843 chr4 55152040 chr22 24176287 chr3 178917005 chr19 1220321 chr10 43613843 chr17 7579472 chr22 24176287 chr19 1220321 chr17 7579472 in Neoplastic and Non-Neoplastic Brain for Each Patient Reference Variant Allele Call Type Tissue Allele Source Gene ID G G Reference A G A G G A A G A A Variant G A G A T G G T Homozygous Homozygous Allele Call Homozygous Homozygous Homozygous Homozygous Homozygous SNP SNP Type SNP SNP SNP SNP SNP Novel Novel Allele Source Novel Hotspot Novel Novel Hotspot Novel EGFR FGFR3 Gene ID FLT3 EGFR HRAS FGFR3 RET FLT3 HRAS RET Reference G TG Reference G G TG A G A G A C A A G C G A T G G T G Variant A GA Variant A A GA G A G A G T G G T A G C T C A C C Allele Call Heterozygous Homozygous Allele Call Heterozygous Homozygous Heterozygous Heterozygous Homozygous Homozygous Heterozygous Heterozygous Heterozygous Homozygous Homozygous Heterozygous Heterozygous Heterozygous Homozygous Homozygous Heterozygous Heterozygous Homozygous Type SNP MNP Type SNP SNP MNP SNP SNP SNP SNP SNP SNP SNP SNP SNP SNP SNP Allele Source Novel Novel Allele Source Novel Novel Novel Hotspot Novel Novel Hotspot Novel Novel Hotspot Hotspot Novel Novel Novel Hotspot Novel Novel Gene ID APC CSF1R Gene ID EGFR APC FGFR3 CSF1R FLT3 EGFR HRAS FGFR3 PDGFRA FLT3 PDGFRA HRAS PIK3CA PDGFRA RET PDGFRA SMARCB1 PIK3CA STK11 RET TP53 SMARCB1 STK11 TP53 CONCLUSIONS All family members demonstrated two common mutaAons in their neoplasAc brain Assue; PDGFRA and HRAS. In addiAon, the two children showed the same SMARCB1 mutaAon. The observaAon that homozygous mutaAons of PDGFRA, HRAS and SMARCB1 genes resulted in early appearance of glioblastoma in the daughter who presented at 6 years of age while heterozygous mutaAons in these genes resulted in the appearance of glioblastoma in her brother more than 10 years later may suggest a criAcal role played by these genes collecAvely in the development of glioblastoma. In comparing the mutaAons present in the neoplasAc and non-‐neoplasAc brain Assue for the father and the son, the son showed the same three mutaAons (PDGFRA, HRAS and SMARCB1) in both neoplasAc and non-‐ neoplasAc brain Assue. The only mutaAon common in the father’s neoplasAc and non-‐neoplasAc brain Assue was HRAS (TP53 and PDGRA mutaAons were not seen in the father’s non-‐neoplasAc brain Assue). IdenAficaAon of significant common mutaAons of isolated familial glioblastoma may aid to proper counseling of families regarding gliomas risk in addiAon to idenAfying new therapeuAc targets.
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