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Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.

Le Gallo M, O'Hara AJ, Rudd ML, Urick ME, Hansen NF, O'Neil NJ, Price JC, Zhang S, England BM, Godwin AK, Sgroi DC, NIH Intramural Sequencing Center (NISC) Comparative Sequencing ProgramHieter P, Mullikin JC, Merino MJ, Bell DW - Nat. Genet. (2012)

Bottom Line: Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually.We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors.We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%).

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, MD, USA.

ABSTRACT
Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.

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Somatic mutations in CHD4, FBXW7, and SPOP cluster within important functional domains of the encoded proteinsSchematic representation of the CHD4, FBXW7, and SPOP proteins showing the positions of individual somatic mutations identified among primary endometrial tumors relative to important functional domains. Mutations in serous (yellow boxes), clear cell (brown boxes), endometrioid (red boxes) and mixed histology (white boxes) endometrial tumors are indicated. (a) 50% of all CHD4 mutations localize within the ATPase/helicase and helicase domains (top). (b) The majority of FBXW7 mutations in endometrial cancer cluster within the WD repeats. The FBXW7-Glu65* and -Lys70fs*27 mutations (not displayed) are within an alternate isoform. (c) All SPOP mutations in endometrial cancer localized to the MATH domain. BTB domain, Broad-complex, Tramtrack and Bric-a-brac domain; D-domain, Dimerization domain; MATH, Meprin and TRAF Homology; NLS, nuclear localization signal; PHD, Plant Homeo Domain-type zinc fingers; WD repeats, tryptophan-aspartic acid repeats.
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Figure 1: Somatic mutations in CHD4, FBXW7, and SPOP cluster within important functional domains of the encoded proteinsSchematic representation of the CHD4, FBXW7, and SPOP proteins showing the positions of individual somatic mutations identified among primary endometrial tumors relative to important functional domains. Mutations in serous (yellow boxes), clear cell (brown boxes), endometrioid (red boxes) and mixed histology (white boxes) endometrial tumors are indicated. (a) 50% of all CHD4 mutations localize within the ATPase/helicase and helicase domains (top). (b) The majority of FBXW7 mutations in endometrial cancer cluster within the WD repeats. The FBXW7-Glu65* and -Lys70fs*27 mutations (not displayed) are within an alternate isoform. (c) All SPOP mutations in endometrial cancer localized to the MATH domain. BTB domain, Broad-complex, Tramtrack and Bric-a-brac domain; D-domain, Dimerization domain; MATH, Meprin and TRAF Homology; NLS, nuclear localization signal; PHD, Plant Homeo Domain-type zinc fingers; WD repeats, tryptophan-aspartic acid repeats.

Mentions: To prioritize our search for novel driver mutations in serous endometrial cancer, we focused on the nine genes that had validated nonsynonymous somatic mutations in more than one tumor (Supplementary Table 7). We resequenced these genes in a prevalence screen of 40 additional serous endometrial tumors. Three of the nine genes (TP53, PIK3CA, and PPP2R1A) have established roles in the pathogenesis of serous endometrial cancer 5-8. Among the 52 serous tumors in our study, TP53, PIK3CA, and PPP2R1A were mutated, respectively, in 71%, 31%, and 25% of tumors, as reported here and in a previous study from our group 6 (Supplementary Table 8 and Supplementary Table 9). The other six genes (CHD4, SPOP, FBXW7, ABCC9, CYP4X1, MAP3K4) have no previously reported role in serous endometrial cancer. The combined discovery and prevalence screens revealed high frequency somatic mutations in CHD4 (17%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%), ABCC9 (6%), and CYP4X1 (4%) (Table 1, Figure 1, Supplementary Table 9, Supplementary Figure 3, and Supplementary Figure 4). The mutation rates for CHD4, FBXW7, and SPOP were significantly higher than the background mutation rate (q ≤0.0353) (Supplementary Table 10).


Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.

Le Gallo M, O'Hara AJ, Rudd ML, Urick ME, Hansen NF, O'Neil NJ, Price JC, Zhang S, England BM, Godwin AK, Sgroi DC, NIH Intramural Sequencing Center (NISC) Comparative Sequencing ProgramHieter P, Mullikin JC, Merino MJ, Bell DW - Nat. Genet. (2012)

Somatic mutations in CHD4, FBXW7, and SPOP cluster within important functional domains of the encoded proteinsSchematic representation of the CHD4, FBXW7, and SPOP proteins showing the positions of individual somatic mutations identified among primary endometrial tumors relative to important functional domains. Mutations in serous (yellow boxes), clear cell (brown boxes), endometrioid (red boxes) and mixed histology (white boxes) endometrial tumors are indicated. (a) 50% of all CHD4 mutations localize within the ATPase/helicase and helicase domains (top). (b) The majority of FBXW7 mutations in endometrial cancer cluster within the WD repeats. The FBXW7-Glu65* and -Lys70fs*27 mutations (not displayed) are within an alternate isoform. (c) All SPOP mutations in endometrial cancer localized to the MATH domain. BTB domain, Broad-complex, Tramtrack and Bric-a-brac domain; D-domain, Dimerization domain; MATH, Meprin and TRAF Homology; NLS, nuclear localization signal; PHD, Plant Homeo Domain-type zinc fingers; WD repeats, tryptophan-aspartic acid repeats.
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Related In: Results  -  Collection

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Figure 1: Somatic mutations in CHD4, FBXW7, and SPOP cluster within important functional domains of the encoded proteinsSchematic representation of the CHD4, FBXW7, and SPOP proteins showing the positions of individual somatic mutations identified among primary endometrial tumors relative to important functional domains. Mutations in serous (yellow boxes), clear cell (brown boxes), endometrioid (red boxes) and mixed histology (white boxes) endometrial tumors are indicated. (a) 50% of all CHD4 mutations localize within the ATPase/helicase and helicase domains (top). (b) The majority of FBXW7 mutations in endometrial cancer cluster within the WD repeats. The FBXW7-Glu65* and -Lys70fs*27 mutations (not displayed) are within an alternate isoform. (c) All SPOP mutations in endometrial cancer localized to the MATH domain. BTB domain, Broad-complex, Tramtrack and Bric-a-brac domain; D-domain, Dimerization domain; MATH, Meprin and TRAF Homology; NLS, nuclear localization signal; PHD, Plant Homeo Domain-type zinc fingers; WD repeats, tryptophan-aspartic acid repeats.
Mentions: To prioritize our search for novel driver mutations in serous endometrial cancer, we focused on the nine genes that had validated nonsynonymous somatic mutations in more than one tumor (Supplementary Table 7). We resequenced these genes in a prevalence screen of 40 additional serous endometrial tumors. Three of the nine genes (TP53, PIK3CA, and PPP2R1A) have established roles in the pathogenesis of serous endometrial cancer 5-8. Among the 52 serous tumors in our study, TP53, PIK3CA, and PPP2R1A were mutated, respectively, in 71%, 31%, and 25% of tumors, as reported here and in a previous study from our group 6 (Supplementary Table 8 and Supplementary Table 9). The other six genes (CHD4, SPOP, FBXW7, ABCC9, CYP4X1, MAP3K4) have no previously reported role in serous endometrial cancer. The combined discovery and prevalence screens revealed high frequency somatic mutations in CHD4 (17%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%), ABCC9 (6%), and CYP4X1 (4%) (Table 1, Figure 1, Supplementary Table 9, Supplementary Figure 3, and Supplementary Figure 4). The mutation rates for CHD4, FBXW7, and SPOP were significantly higher than the background mutation rate (q ≤0.0353) (Supplementary Table 10).

Bottom Line: Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually.We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors.We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%).

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, MD, USA.

ABSTRACT
Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.

Show MeSH
Related in: MedlinePlus