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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

Mutational landscape of MOTs identified by exome sequencing. Samples are grouped according to pathological classification and ordered from lowest to highest mutation frequency. a Somatic mutation frequency (left Y-axis) and number of coding mutations by consequence (right Y-axis). b Relative frequency of somatic mutations according to base substitution type. Substitutions were categorized by the six possible base-pair changes
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Fig1: Mutational landscape of MOTs identified by exome sequencing. Samples are grouped according to pathological classification and ordered from lowest to highest mutation frequency. a Somatic mutation frequency (left Y-axis) and number of coding mutations by consequence (right Y-axis). b Relative frequency of somatic mutations according to base substitution type. Substitutions were categorized by the six possible base-pair changes

Mentions: To profile the somatic mutation spectrum of mucinous tumors of the ovary, we performed whole exome sequencing on 24 tumors including 5 benign cystadenomas, 8 borderline tumors and 11 carcinomas (Table 1, Additional file 1: Table S1). A mean coverage depth of 144× was achieved in both neoplastic and non-cancerous specimens (range 53-fold to 224-fold) and 91 % of the bases were covered by at least 20 uniquely mapping reads (Additional file 1: Table S2). Using stringent criteria, 1126 somatic coding and essential splice site mutations were identified (1031 SNVs and 95 indels), of which 841 were predicted to alter protein sequence (Additional file 1: Table S3). These included 44 (5.2 %) nonsense, 60 (7.1 %) frameshift indel, 16 (1.9 %) splice site, 27 (3.2 %) inframe indel and 694 (82.5 %) missense mutations. Benign and borderline tumors had on average 25.4 (range 21–38) and 32.9 (range 2–76) coding mutations per tumor, equating to a frequency of 0.8 mutations/Mb and 0.9 mutations/Mb respectively. Although variable, this mutation burden did not differ between benign and borderline tumors but was significantly lower when compared to the carcinomas (average of 66.9 mutations per sample and 1.5 mutations/Mb) (P = 0.008 vs. benign and P = 0.047 vs. borderline) attributed mostly to an accumulation of missense mutations in the carcinomas (Fig. 1a, Additional file 1: Table S5). There were no hyper-mutated cases (defined as >10 mutations/Mb) indicative of a mutator phenotype such as mismatch repair deficiency. Relative to other cancer types, MOTs showed a similar somatic mutation density to breast, serous ovarian and pancreatic cancers, but a lower density than colorectal and stomach tumors [14, 15].Table 1


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)

Mutational landscape of MOTs identified by exome sequencing. Samples are grouped according to pathological classification and ordered from lowest to highest mutation frequency. a Somatic mutation frequency (left Y-axis) and number of coding mutations by consequence (right Y-axis). b Relative frequency of somatic mutations according to base substitution type. Substitutions were categorized by the six possible base-pair changes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Mutational landscape of MOTs identified by exome sequencing. Samples are grouped according to pathological classification and ordered from lowest to highest mutation frequency. a Somatic mutation frequency (left Y-axis) and number of coding mutations by consequence (right Y-axis). b Relative frequency of somatic mutations according to base substitution type. Substitutions were categorized by the six possible base-pair changes
Mentions: To profile the somatic mutation spectrum of mucinous tumors of the ovary, we performed whole exome sequencing on 24 tumors including 5 benign cystadenomas, 8 borderline tumors and 11 carcinomas (Table 1, Additional file 1: Table S1). A mean coverage depth of 144× was achieved in both neoplastic and non-cancerous specimens (range 53-fold to 224-fold) and 91 % of the bases were covered by at least 20 uniquely mapping reads (Additional file 1: Table S2). Using stringent criteria, 1126 somatic coding and essential splice site mutations were identified (1031 SNVs and 95 indels), of which 841 were predicted to alter protein sequence (Additional file 1: Table S3). These included 44 (5.2 %) nonsense, 60 (7.1 %) frameshift indel, 16 (1.9 %) splice site, 27 (3.2 %) inframe indel and 694 (82.5 %) missense mutations. Benign and borderline tumors had on average 25.4 (range 21–38) and 32.9 (range 2–76) coding mutations per tumor, equating to a frequency of 0.8 mutations/Mb and 0.9 mutations/Mb respectively. Although variable, this mutation burden did not differ between benign and borderline tumors but was significantly lower when compared to the carcinomas (average of 66.9 mutations per sample and 1.5 mutations/Mb) (P = 0.008 vs. benign and P = 0.047 vs. borderline) attributed mostly to an accumulation of missense mutations in the carcinomas (Fig. 1a, Additional file 1: Table S5). There were no hyper-mutated cases (defined as >10 mutations/Mb) indicative of a mutator phenotype such as mismatch repair deficiency. Relative to other cancer types, MOTs showed a similar somatic mutation density to breast, serous ovarian and pancreatic cancers, but a lower density than colorectal and stomach tumors [14, 15].Table 1

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