Deep Genetic Connection Between Cancer and Developmental Disorders

Qi, Hongjian; Dong, Chengliang; Chung, Wendy K.; Wang, Kai; Shen, Yufeng

doi:10.1002/humu.23040

Cited by 31 publications

(34 citation statements)

References 56 publications

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“…, logistic regression correcting for shet), as observed previously 28,29 , as well as a significant enrichment of nonsynonymous DNMs in these genes (Supplementary Table 9). This overlap extends to somatic driver mutations: we observe 117 DNMs at 76 recurrent somatic mutations observed in at least three patients in The Cancer Genome Atlas (TCGA) 30 Fig.…”

supporting

confidence: 77%

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Kaplanis¹,

Samocha²,

Wiel³

et al. 2020

Nature

422

532

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De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

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supporting

confidence: 77%

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Kaplanis¹,

Samocha²,

Wiel³

et al. 2020

Nature

422

532

View full text Add to dashboard Cite

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“…We observed a significant overlap between the 299 DNM-enriched DD-associated genes 152 and a set of 369 previously described cancer driver genes 25 (p = 1.7 x 10 -46 , logistic regression 153 correcting for shet), as observed previously 26,27 , as well as a significant enrichment of 154 nonsynonymous DNMs in these genes ( Supplementary Table 9). This overlap extends to 155 somatic driver mutations: we observe 117 DNMs at 76 recurrent somatic mutations observed in 156 at least three patients in The Cancer Genome Atlas (TCGA) 28 Fig.…”

supporting

confidence: 67%

Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Kaplanis

Samocha

Wiel

et al. 2019

Preprint

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1De novo mutations (DNMs) in protein-coding genes are a well-established cause of 2 developmental disorders (DD). However, known DD-associated genes only account for a 3 minority of the observed excess of such DNMs. To identify novel DD-associated genes, we 4 integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and 5 developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We 6 identified 299 significantly DD-associated genes, including 49 not previously robustly associated 7 with DDs. Despite detecting more DD-associated genes than in any previous study, much of the 8 excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that 9 over 500 novel DD-associated genes await discovery, many of which are likely to be less 10 penetrant than the currently known genes. Research access to clinical diagnostic datasets will 11 be critical for completing the map of dominant DDs. 12 13

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“…Damaging CR variants are increased in individuals with developmental delays. Because these delays can occur with CHD, we partitioned patients into those with extracardiac anomalies (ECA; n = 1482), neurodevelopmental defects (NDD; n = 1393), both ECA and NDD (n = 878), and neither ECA or NDD (isolated CHD; n = 1379). The LoF variants in CR genes were highest among patients with CHD and ECA (CHD: 248 of 1482 individuals [16.7%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.59 [95% CI, 1.37-1.85]; P = 1.3 × 10 −10 ; eTable 9 in the Supplement ) and patients with CHD and NDD (CHD: 209 of 1393 individuals [15.0%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.40 [95% CI, 1.19-1.64]; P = 9.6 × 10 −6 ), while the LoF in CR genes in patients with isolated CHD was comparable with that of control participants.…”

Section: Resultsmentioning

confidence: 99%

Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease

et al. 2021

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IMPORTANCE Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions. OBJECTIVE To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants. DESIGN, SETTING, AND PARTICIPANTS This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019. EXPOSURES Presence of rare (allele frequency, <1 × 10 −5) loss-of-function (LoF) variants in cancer risk genes. MAIN OUTCOMES AND MEASURES Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer-Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants. RESULTS A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10 −12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10 −16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and

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Deep Genetic Connection Between Cancer and Developmental Disorders

Cited by 31 publications

References 56 publications

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease

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