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Article
Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade
Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia developme...
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Article
Open AccessDramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge
Poorly differentiated pancreatic neuroendocrine tumors (PDNEC), are a subtype of pancreatic cancer encompassing both small cell and large cell neuroendocrine carcinoma subtypes, and are characterized as distin...
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Article
Open AccessExpanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations
Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify heredita...
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Article
Open AccessReversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies
The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers ...
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Article
Open AccessMethylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of “Second Hit” in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5–6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-r...
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Article
Open AccessDiagnostic yield and clinical relevance of expanded genetic testing for cancer patients
Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary c...
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Article
The context-specific role of germline pathogenicity in tumorigenesis
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we ...
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Article
Open AccessGermline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination
Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function...
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Article
Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors
The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 patients with solid tumors who underwent prospective matched tumor–normal DNA sequencing with downstream...
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Article
Cancer therapy shapes the fitness landscape of clonal hematopoiesis
Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of...
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Article
Author Correction: Tumour lineage shapes BRCA-mediated phenotypes
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Article
Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms
Histiocytoses are clonal hematopoietic disorders frequently driven by mutations map** to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not...
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Article
Tumour lineage shapes BRCA-mediated phenotypes
Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1–3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-...
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Article
A synonymous germline variant PALB2 c.18G>T (p.Gly6=) disrupts normal splicing in a family with pancreatic and breast cancers
Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 synonymous variant c.18G>T (p.Gly6=) identified in a family with pancr...
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Article
Open AccessRefractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing
Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecular alterations found in patients’ tumors. These testing results have the potential to affect clinical care by g...
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Structural Effects of Oncogenic PI3Kα Mutations
Physiological activation of PI3Kα is brought about by the release of the inhibition by p85 when the nSH2 binds the phosphorylated tyrosine of activated receptors or their substrates. Oncogenic mutations of PI3...
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Article
Structural comparisons of class I phosphoinositide 3-kinases
The recent determination of the structure of the class I phosphoinositide 3-kinase PI3Kα has identified important structural differences between the class 1 PI3Ks. How can this information be used to improve c...
