The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge
. Recent advances in interpretability of ...machine learning models as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics
. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
Inherited DNA-Repair Defects in Colorectal Cancer AlDubayan, Saud H.; Giannakis, Marios; Moore, Nathanael D. ...
American journal of human genetics,
03/2018, Letnik:
102, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline ...mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi).
The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline ...features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8+ T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
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•Tumor immune infiltration impacts response to immunotherapy•GWAS identifies inherited genetic variants associated with immune infiltration•Aggregating variants into genes and networks increases power to find associations•Germline associations may offer insight into predictors of response to immunotherapy
The role of inherited variants in influencing the immune composition of the tumor microenvironment is not fully characterized. Shahamatdar et al. identify germline variants, genes, and pathways associated with immune infiltration phenotypes in cancer, which may offer insights into determinants of response to immunotherapy.
More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants ...in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Findings in Ewing sarcoma were validated with an additional cohort of 430 individuals, and a subset of 301 Ewing sarcoma parent-proband trios was analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals, OR 12.6, 95% CI 3.0–43.2, p = 0.003, FDR = 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals, OR 7.0, 95% CI 1.7–23.6, p = 0.014), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in individuals with Ewing sarcoma. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severely debilitating disorder caused by pathogenic variants in COL7A1 and is characterized by extreme skin fragility, chronic inflammation, and ...fibrosis. A majority of patients with RDEB develop squamous cell carcinoma, a highly aggressive skin cancer with limited treatment options currently available. In this study, we utilized an approach leveraging whole-genome sequencing and RNA sequencing across 3 different tissues in a single patient with RDEB to gain insight into possible mechanisms of RDEB-associated squamous cell carcinoma progression and to identify potential therapeutic options. As a result, we identified PLK-1 as a possible candidate for targeted therapy and discovered microsatellite instability and accelerated aging as factors potentially contributing to the aggressive nature and early onset of RDEB squamous cell carcinoma. By integrating multitissue genomic and transcriptomic analyses in a single patient, we demonstrate the promise of bridging the gap between genomic research and clinical applications for developing tailored therapies for patients with rare genetic disorders such as RDEB.
IMPORTANCE: Less than 10% of patients with cancer have detectable pathogenic germline alterations, which may be partially due to incomplete pathogenic variant detection. OBJECTIVE: To evaluate if ...deep learning approaches identify more germline pathogenic variants in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of a standard germline detection method and a deep learning method in 2 convenience cohorts with prostate cancer and melanoma enrolled in the US and Europe between 2010 and 2017. The final date of clinical data collection was December 2017. EXPOSURES: Germline variant detection using standard or deep learning methods. MAIN OUTCOMES AND MEASURES: The primary outcomes included pathogenic variant detection performance in 118 cancer-predisposition genes estimated as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The secondary outcomes were pathogenic variant detection performance in 59 genes deemed actionable by the American College of Medical Genetics and Genomics (ACMG) and 5197 clinically relevant mendelian genes. True sensitivity and true specificity could not be calculated due to lack of a criterion reference standard, but were estimated as the proportion of true-positive variants and true-negative variants, respectively, identified by each method in a reference variant set that consisted of all variants judged to be valid from either approach. RESULTS: The prostate cancer cohort included 1072 men (mean SD age at diagnosis, 63.7 7.9 years; 857 79.9% with European ancestry) and the melanoma cohort included 1295 patients (mean SD age at diagnosis, 59.8 15.6 years; 488 37.7% women; 1060 81.9% with European ancestry). The deep learning method identified more patients with pathogenic variants in cancer-predisposition genes than the standard method (prostate cancer: 198 vs 182; melanoma: 93 vs 74); sensitivity (prostate cancer: 94.7% vs 87.1% difference, 7.6%; 95% CI, 2.2% to 13.1%; melanoma: 74.4% vs 59.2% difference, 15.2%; 95% CI, 3.7% to 26.7%), specificity (prostate cancer: 64.0% vs 36.0% difference, 28.0%; 95% CI, 1.4% to 54.6%; melanoma: 63.4% vs 36.6% difference, 26.8%; 95% CI, 17.6% to 35.9%), PPV (prostate cancer: 95.7% vs 91.9% difference, 3.8%; 95% CI, –1.0% to 8.4%; melanoma: 54.4% vs 35.4% difference, 19.0%; 95% CI, 9.1% to 28.9%), and NPV (prostate cancer: 59.3% vs 25.0% difference, 34.3%; 95% CI, 10.9% to 57.6%; melanoma: 80.8% vs 60.5% difference, 20.3%; 95% CI, 10.0% to 30.7%). For the ACMG genes, the sensitivity of the 2 methods was not significantly different in the prostate cancer cohort (94.9% vs 90.6% difference, 4.3%; 95% CI, –2.3% to 10.9%), but the deep learning method had a higher sensitivity in the melanoma cohort (71.6% vs 53.7% difference, 17.9%; 95% CI, 1.82% to 34.0%). The deep learning method had higher sensitivity in the mendelian genes (prostate cancer: 99.7% vs 95.1% difference, 4.6%; 95% CI, 3.0% to 6.3%; melanoma: 91.7% vs 86.2% difference, 5.5%; 95% CI, 2.2% to 8.8%). CONCLUSIONS AND RELEVANCE: Among a convenience sample of 2 independent cohorts of patients with prostate cancer and melanoma, germline genetic testing using deep learning, compared with the current standard genetic testing method, was associated with higher sensitivity and specificity for detection of pathogenic variants. Further research is needed to understand the relevance of these findings with regard to clinical outcomes.
This study demonstrates that germline mutations in the TP53 gene are likely to predispose men to prostate cancer. Current Li-Fraumeni syndrome screening guidelines should be updated to consider ...annual prostate cancer screening, and TP53 should be considered in germline prostate cancer susceptibility testing.
Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.
To determine whether gTP53 predisposes to prostate cancer.
This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.
We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.
We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range IQR) of 3.0 (1.3–7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval CI 9.2–55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2–14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51–62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.
Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.
Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.
Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor ...microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β
-microglobulin (
), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.
Background Breast cancer patients from the indigenous Arab population present much earlier than patients from Western countries and have traditionally been underrepresented in cancer genomics ...studies. The contribution of polygenic and Mendelian risk toward the earlier onset of breast cancer in the population remains elusive. Methods We performed low-pass whole genome sequencing (lpWGS) and whole-exome sequencing (WES) from 220 female breast cancer patients unselected for positive family history from the indigenous Arab population. Using publicly available resources, we imputed population-specific variants and calculated breast cancer burden-sensitive polygenic risk scores (PRS). Variant pathogenicity was also evaluated on exome variants with high coverage. Results Variants imputed from lpWGS showed high concordance with paired exome (median dosage correlation: 0.9459, Interquartile range: 0.9410-0.9490). After adjusting the PRS to the Arab population, we found significant associations between PRS performance in risk prediction and first-degree relative breast cancer history prediction (Spearman rho=0.43, p = 0.03), where breast cancer patients in the top PRS decile are 5.53 (95% CI 1.76-17.97, p = 0.003) times more likely also to have a first-degree relative diagnosed with breast cancer compared to those in the middle deciles. In addition, we found evidence for the genetic liability threshold model of breast cancer where among patients with a family history of breast cancer, pathogenic rare variant carriers had significantly lower PRS than non-carriers (p = 0.0205, Mann-Whitney U test) while for non-carriers every standard deviation increase in PRS corresponded to 4.52 years (95% CI 8.88-0.17, p = 0.042) earlier age of presentation. Conclusions Overall, our study provides a framework to assess polygenic risk in an understudied population using lpWGS and identifies common variant risk as a factor independent of pathogenic variant carrier status for earlier age of onset of breast cancer among indigenous Arab breast cancer patients. Keywords: Low-pass whole genome sequencing, Imputation, Polygenic risk score, Breast cancer, Arab population, Age of onset, Pathogenic variants
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