The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome
Summary: Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus canc...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247723000313 |
| _version_ | 1827950733270450176 |
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| author | Ruipeng Wei Lamis Yehia Ying Ni Charis Eng |
| author_facet | Ruipeng Wei Lamis Yehia Ying Ni Charis Eng |
| author_sort | Ruipeng Wei |
| collection | DOAJ |
| description | Summary: Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10−3 in all samples; p = 4.2 × 10−3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10−2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10−2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS. |
| first_indexed | 2024-04-09T13:30:08Z |
| format | Article |
| id | doaj.art-e7c8df4c90a34e4bb49f13c40e69ed46 |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-04-09T13:30:08Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-e7c8df4c90a34e4bb49f13c40e69ed462023-05-10T04:19:56ZengElsevierHGG Advances2666-24772023-07-0143100199The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndromeRuipeng Wei0Lamis Yehia1Ying Ni2Charis Eng3Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USACenter for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USAGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Corresponding authorSummary: Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10−3 in all samples; p = 4.2 × 10−3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10−2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10−2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.http://www.sciencedirect.com/science/article/pii/S2666247723000313PTENgenomic modifiersmitochondrial DNA (mtDNA)autism spectrum disordercancer |
| spellingShingle | Ruipeng Wei Lamis Yehia Ying Ni Charis Eng The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome HGG Advances PTEN genomic modifiers mitochondrial DNA (mtDNA) autism spectrum disorder cancer |
| title | The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome |
| title_full | The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome |
| title_fullStr | The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome |
| title_full_unstemmed | The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome |
| title_short | The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome |
| title_sort | mitochondrial genome as a modifier of autism versus cancer phenotypes in pten hamartoma tumor syndrome |
| topic | PTEN genomic modifiers mitochondrial DNA (mtDNA) autism spectrum disorder cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2666247723000313 |
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