The context-specific role of germline pathogenicity in tumorigenesis

Srinivasan, Preethi; Bandlamudi, Chaitanya; Jonsson, Philip; Kemel, Yelena; Chavan, Shweta S.; Richards, Allison L.; Penson, A.; Bielski, Craig M.; Fong, Christopher J.; Syed, Aijazuddin; Jayakumaran, Gowtham; Prasad, Meera; Hwee, Jason; Sumer, S. Onur; Bruijn, Ino de; Li, Xiang; Gao, Jianjiong; Schultz, Nikolaus; Cambria, Roy; Galle, Jesse; Mukherjee, Semanti; Vijai, Joseph; Cadoo, Karen A.; Carlo, Maria I.; Walsh, Michael F.; Mandelker, Diana; Ceyhan‐Birsoy, Ozge; Shia, Jinru; Zehir, Ahmet; Ladanyi, Marc; Hyman, David M.; Zhang, Liying; Offit, Kenneth; Robson, Mark E.; Solit, David B.; Stadler, Zsofia K.; Berger, Michael F.; Taylor, Barry S.

doi:10.1038/s41588-021-00949-1

Cited by 55 publications

(62 citation statements)

References 59 publications

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“…Considering the proportion of replicated hits to the number of re-tested hits, the validation rate was ~2.5 times higher for the recessive model (Supplementary Fig. 12e ), which was expected since many DNA repair genes are likely haplosufficient 63 , 64 .…”

Section: Resultsmentioning

confidence: 85%

The impact of rare germline variants on human somatic mutation processes

2022

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Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

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Section: Resultsmentioning

confidence: 85%

The impact of rare germline variants on human somatic mutation processes

2022

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“…63,64 In regards to this, the recently created SignalDB constitutes a good example of a useful resource that provides information about pathogenic germline variants and their corresponding tumor-specific zygosity changes stratified by gene, lineage, and cancer type based on a large clinical cohort of patients sequenced with NGS panels. 33 When it comes to prognosis, NGS panels can be used within the clinical setting to identify biomarkers with FDA or professional guideline-recognized prognostic implications such as those curated by the OncoKB knowledge base in hematological malignancies. 28 More generally, certain machine learning tools like Oncocast 65 have been designed to build personalized profiles that integrate clinical and genomic features derived from NGS data for risk stratification and prediction of recurrence.…”

Section: Targeted Ngs Panels In Cancer Research and Clinical Carementioning

confidence: 99%

“…Furthermore, targeted NGS panels can be used to identify germline variants in cancer predisposition genes and provide clinically actionable information for risk reduction in family members, reproductive planning, and selection of targeted therapies 63,64 . In regards to this, the recently created SignalDB constitutes a good example of a useful resource that provides information about pathogenic germline variants and their corresponding tumor‐specific zygosity changes stratified by gene, lineage, and cancer type based on a large clinical cohort of patients sequenced with NGS panels 33 . When it comes to prognosis, NGS panels can be used within the clinical setting to identify biomarkers with FDA or professional guideline‐recognized prognostic implications such as those curated by the OncoKB knowledge base in hematological malignancies 28 .…”

Section: Targeted Ngs Panels In Cancer Research and Clinical Carementioning

confidence: 99%

Computational methods and translational applications for targeted next‐generation sequencing platforms

Luthra

Mastrogiacomo

Smith

et al. 2022

Genes Chromosomes & Cancer

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During the past decade, next-generation sequencing (NGS) technologies have become widely adopted in cancer research and clinical care. Common applications within the clinical setting include patient stratification into relevant molecular subtypes, identification of biomarkers of response and resistance to targeted and systemic therapies, assessment of heritable cancer risk based on known pathogenic variants, and longitudinal monitoring of treatment response. The need for efficient downstream processing and reliable interpretation of sequencing data has led to the development of novel algorithms and computational pipelines, as well as structured knowledge bases that link genomic alterations to currently available drugs and ongoing clinical trials. Cancer centers around the world use different types of targeted solid-tissue and blood based NGS assays to analyze the genomic and transcriptomic profile of patients as part of their routine clinical care. Recently, cross-institutional collaborations have led to the creation of large pooled datasets that can offer valuable insights into the genomics of rare cancers.

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“…A single paper analyzed the genome of several metachronous tumors in a BAP1 -TPDS patient [ 29 ]. In a recent study involving 17,152 patients with different tumor types, Srinivasan et al reported some information of the somatic genome of six patients with TPDS [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience

et al. 2022

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Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

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The context-specific role of germline pathogenicity in tumorigenesis

Cited by 55 publications

References 59 publications

The impact of rare germline variants on human somatic mutation processes

The impact of rare germline variants on human somatic mutation processes

Computational methods and translational applications for targeted next‐generation sequencing platforms

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience

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