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Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors.

Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, Australian Ovarian Cancer Study GroupCampbell IG, Gorringe KL - Genome Med (2015)

Bottom Line: They are thought to be molecularly distinct from other ovarian tumors but there have been no exome-level sequencing studies performed to date.The predominant mutational signature was of C>T transitions in a NpCpG context, indicative of deamination of methyl-cytosines.As well as mutations in known drivers (KRAS, BRAF and CDKN2A), we identified a high percentage of carcinomas with TP53 mutations (52 %), and recurrent mutations in RNF43, ELF3, GNAS, ERBB3 and KLF5.

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria Australia.

ABSTRACT

Background: Mucinous ovarian tumors are an unusual group of rare neoplasms with an apparently clear progression from benign to borderline to carcinoma, yet with a controversial cell of origin in the ovarian surface epithelium. They are thought to be molecularly distinct from other ovarian tumors but there have been no exome-level sequencing studies performed to date.

Methods: To understand the genetic etiology of mucinous ovarian tumors and assess the presence of novel therapeutic targets or pathways, we undertook exome sequencing of 24 tumors encompassing benign (5), borderline (8) and carcinoma (11) histologies and also assessed a validation cohort of 58 tumors for specific gene regions including exons 4-9 of TP53.

Results: The predominant mutational signature was of C>T transitions in a NpCpG context, indicative of deamination of methyl-cytosines. As well as mutations in known drivers (KRAS, BRAF and CDKN2A), we identified a high percentage of carcinomas with TP53 mutations (52 %), and recurrent mutations in RNF43, ELF3, GNAS, ERBB3 and KLF5.

Conclusions: The diversity of mutational targets suggests multiple routes to tumorigenesis in this heterogeneous group of tumors that is generally distinct from other ovarian subtypes.

No MeSH data available.


Related in: MedlinePlus

Distribution of somatic mutations identified in novel significantly mutated genes. ELF3, KLF5, GNAS and ERBB3 are shown in the context of protein domains as predicted by UniProt, with somatic mutations identified in the exome (closed circle) and validation (open circle) cohorts mapped to each gene. I-IV extracellular domains I, II, III and IV, AT hook & NLS AT-hook domain and nuclear localization signal, C2H2 zinc-finger C2H2 domain, ETS DNA binding domain, GTP GTP nucleotide binding region, PNT pointed domain, SAR serine-rich and aspartic acid-rich domain, TAD transactivation domain, TKD tyrosine kinase domain
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Fig3: Distribution of somatic mutations identified in novel significantly mutated genes. ELF3, KLF5, GNAS and ERBB3 are shown in the context of protein domains as predicted by UniProt, with somatic mutations identified in the exome (closed circle) and validation (open circle) cohorts mapped to each gene. I-IV extracellular domains I, II, III and IV, AT hook & NLS AT-hook domain and nuclear localization signal, C2H2 zinc-finger C2H2 domain, ETS DNA binding domain, GTP GTP nucleotide binding region, PNT pointed domain, SAR serine-rich and aspartic acid-rich domain, TAD transactivation domain, TKD tyrosine kinase domain

Mentions: Three mutations in the epithelial-specific ETS transcription factor E74-like factor 3 (ELF3) were detected in three tumors by exome sequencing. ELF3 was significantly mutated above background (MuSiC) and had an excess of likely deleterious mutations (OncodriveFM) including two frameshift insertions (p.Val345Glyfs*126, p.Asp239Glyfs*62) and a missense substitution (p.Met324Val) (Table 2, Figs. 2 and 3). Sequencing of the coding regions in the expanded cohort identified an additional splice site mutation in a borderline tumor (c.1001 + 1_1001 + 2insGG). Although ELF3 is thus infrequently mutated (6.9 % borderline tumors and 6.5 % carcinomas), the shared characteristics of the four heterozygous mutations is indicative of a pathogenic role. Three of the mutations are overtly deleterious, including two frameshift indels and a canonical splice site mutation, while the missense mutation is predicted to be deleterious by computational analyses [20–22]. We further investigated the exon 8 splice donor site mutation by cDNA sequencing, which confirmed the use of an alternative donor splice sequence in the mutant allele (Additional file 2: Figure S4) consistent with the in silico prediction [23]. This mutation would result in out-of-frame, continued translation into the 3′-untranslated region (p.Tyr335Glyfs*113). cDNA sequencing of this and the two other truncating mutations found that all three mutations were readily detected in the tumor RNA, indicating that these mutations are not the subject of strong nonsense-mediated decay (Additional file 2: Figure S4). Truncating mutations in this epithelial-specific transcription factor have recently been reported in other cancers, including cancer of the cervix, stomach and bladder [24–26]. Interestingly, ELF3-mutated cervical carcinomas express ELF3 at a higher level compared to wild-type tumors [24]. This result may suggest that both copies of this gene are required and mutation of one allele results in up-regulation of the gene in an attempt to compensate. Alternatively, ELF3 mutations may only have a selective advantage in tumors highly expressing ELF3.Fig. 3


Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors.

Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, Australian Ovarian Cancer Study GroupCampbell IG, Gorringe KL - Genome Med (2015)

Distribution of somatic mutations identified in novel significantly mutated genes. ELF3, KLF5, GNAS and ERBB3 are shown in the context of protein domains as predicted by UniProt, with somatic mutations identified in the exome (closed circle) and validation (open circle) cohorts mapped to each gene. I-IV extracellular domains I, II, III and IV, AT hook & NLS AT-hook domain and nuclear localization signal, C2H2 zinc-finger C2H2 domain, ETS DNA binding domain, GTP GTP nucleotide binding region, PNT pointed domain, SAR serine-rich and aspartic acid-rich domain, TAD transactivation domain, TKD tyrosine kinase domain
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528310&req=5

Fig3: Distribution of somatic mutations identified in novel significantly mutated genes. ELF3, KLF5, GNAS and ERBB3 are shown in the context of protein domains as predicted by UniProt, with somatic mutations identified in the exome (closed circle) and validation (open circle) cohorts mapped to each gene. I-IV extracellular domains I, II, III and IV, AT hook & NLS AT-hook domain and nuclear localization signal, C2H2 zinc-finger C2H2 domain, ETS DNA binding domain, GTP GTP nucleotide binding region, PNT pointed domain, SAR serine-rich and aspartic acid-rich domain, TAD transactivation domain, TKD tyrosine kinase domain
Mentions: Three mutations in the epithelial-specific ETS transcription factor E74-like factor 3 (ELF3) were detected in three tumors by exome sequencing. ELF3 was significantly mutated above background (MuSiC) and had an excess of likely deleterious mutations (OncodriveFM) including two frameshift insertions (p.Val345Glyfs*126, p.Asp239Glyfs*62) and a missense substitution (p.Met324Val) (Table 2, Figs. 2 and 3). Sequencing of the coding regions in the expanded cohort identified an additional splice site mutation in a borderline tumor (c.1001 + 1_1001 + 2insGG). Although ELF3 is thus infrequently mutated (6.9 % borderline tumors and 6.5 % carcinomas), the shared characteristics of the four heterozygous mutations is indicative of a pathogenic role. Three of the mutations are overtly deleterious, including two frameshift indels and a canonical splice site mutation, while the missense mutation is predicted to be deleterious by computational analyses [20–22]. We further investigated the exon 8 splice donor site mutation by cDNA sequencing, which confirmed the use of an alternative donor splice sequence in the mutant allele (Additional file 2: Figure S4) consistent with the in silico prediction [23]. This mutation would result in out-of-frame, continued translation into the 3′-untranslated region (p.Tyr335Glyfs*113). cDNA sequencing of this and the two other truncating mutations found that all three mutations were readily detected in the tumor RNA, indicating that these mutations are not the subject of strong nonsense-mediated decay (Additional file 2: Figure S4). Truncating mutations in this epithelial-specific transcription factor have recently been reported in other cancers, including cancer of the cervix, stomach and bladder [24–26]. Interestingly, ELF3-mutated cervical carcinomas express ELF3 at a higher level compared to wild-type tumors [24]. This result may suggest that both copies of this gene are required and mutation of one allele results in up-regulation of the gene in an attempt to compensate. Alternatively, ELF3 mutations may only have a selective advantage in tumors highly expressing ELF3.Fig. 3

Bottom Line: They are thought to be molecularly distinct from other ovarian tumors but there have been no exome-level sequencing studies performed to date.The predominant mutational signature was of C>T transitions in a NpCpG context, indicative of deamination of methyl-cytosines.As well as mutations in known drivers (KRAS, BRAF and CDKN2A), we identified a high percentage of carcinomas with TP53 mutations (52 %), and recurrent mutations in RNF43, ELF3, GNAS, ERBB3 and KLF5.

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria Australia.

ABSTRACT

Background: Mucinous ovarian tumors are an unusual group of rare neoplasms with an apparently clear progression from benign to borderline to carcinoma, yet with a controversial cell of origin in the ovarian surface epithelium. They are thought to be molecularly distinct from other ovarian tumors but there have been no exome-level sequencing studies performed to date.

Methods: To understand the genetic etiology of mucinous ovarian tumors and assess the presence of novel therapeutic targets or pathways, we undertook exome sequencing of 24 tumors encompassing benign (5), borderline (8) and carcinoma (11) histologies and also assessed a validation cohort of 58 tumors for specific gene regions including exons 4-9 of TP53.

Results: The predominant mutational signature was of C>T transitions in a NpCpG context, indicative of deamination of methyl-cytosines. As well as mutations in known drivers (KRAS, BRAF and CDKN2A), we identified a high percentage of carcinomas with TP53 mutations (52 %), and recurrent mutations in RNF43, ELF3, GNAS, ERBB3 and KLF5.

Conclusions: The diversity of mutational targets suggests multiple routes to tumorigenesis in this heterogeneous group of tumors that is generally distinct from other ovarian subtypes.

No MeSH data available.


Related in: MedlinePlus