AlphaMissense for Identifying Pathogenic Missense Mutations in DNA Damage Repair Genes in Cancer.

Purpose: AlphaMissense is a new artificial intelligence-based approach to predicting the pathogenicity of missense variants. However, whether its predictions can be directly applied to clinical decision making remains unclear. This study aimed to evaluate the accuracy of AlphaMissense predictions for DNA damage repair (DDR) genes using genomic and clinical characteristics.

The cold immunological landscape of ATM-deficient cancers.

Background: Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or DNA polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated () is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of loss on tumor immunogenicity are poorly understood.

Impact of Clonal Hematopoiesis on Solid Tumor Progression Following Radiation Therapy.

Purpose: Clonal hematopoiesis (CH) has been shown to adversely affect outcomes in patients with nonhematologic cancers. However, the effects of CH on response to specific treatments, including radiation therapy (RT), are unknown.

Methods: We analyzed patients with solid tumors harboring nonpathogenic somatic or germline mutations (n = 144) and mutations (n = 270) who received RT and underwent prospective tumor and matched WBC sequencing using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets assay.

Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.

Purpose: The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase.

Increased Synthetic Cytotoxicity of Combinatorial Chemoradiation Therapy in Homologous Recombination Deficient Tumors.

Purpose: Homologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with radiation therapy (RT), leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit.

Most large structural variants in cancer genomes can be detected without long reads.

Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured.

Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers.

ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications.

Background: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified.

Methods: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma.

Germline 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 variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.

Mutations in and differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors.

Synthetic Lethality in Cancer Therapeutics: The Next Generation.

Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes.

Homologous recombination deficiency: how genomic signatures are generated.

Cancer genomes harbor mutational and structural rearrangements that are jointly shaped by DNA damage and repair mechanisms. Accumulating evidence suggests that genetic alterations in DNA repair-defective tumors reflect the scars caused by the use of backup DNA repair mechanisms needed to maintain cellular viability. Detailed analysis of the patterns of mutations and structural rearrangements present in BRCA1/2-deficient tumors has allowed for the delineation of genomic signatures that reflect alternative repair with inactive homologous recombination (HR).

Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.

Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure.

Moving beyond PARP Inhibition in ATM-Deficient Prostate Cancer.

DNA repair defects are found in primary and metastatic prostate cancer. Alterations in the gene are the second most common defect after , but their sensitivity to PARP inhibitors has been questioned by recent clinical literature. The work by Rafiei and colleagues in this issue of now supports this observation with genetically engineered cells and quantitative responses.

The Landscape of Somatic Genetic Alterations in Breast Cancers from Germline Mutation Carriers.

Pathogenic germline variants in checkpoint kinase 2 (), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants).

The therapeutic significance of mutational signatures from DNA repair deficiency in cancer.

Cancer is fundamentally a disease of the genome and inherited deficiencies in DNA repair pathways are well established to increase lifetime cancer risk. Computational analysis of pan-cancer data has identified signatures of mutational processes thought to be responsible for the pattern of mutations in any given cancer. These analyses identified altered DNA repair pathways in a much broader spectrum of cancers than previously appreciated with significant therapeutic implications.

A new role for a tumor-suppressing protein.

In addition to its role in preventing tumors, the protein p53 appears to participate in a DNA repair process known as the replication-stress response.

Modeling Dose Response for Late Dysphagia in Patients With Head and Neck Cancer in the Modern Era of Definitive Chemoradiation.

Purpose: To develop personalized multivariate dose-response models for late dysphagia in patients with head and neck cancer treated in the modern era of combined chemotherapy with intensity-modulated radiation therapy.

Patients And Methods: The analysis included 424 patients (oropharyngeal cancer [n = 295] and nasopharyngeal, hypopharyngeal, or laryngeal cancer [n = 129]) who received definitive chemoradiation between January 2004 and April 2009. The superior, middle, and inferior pharyngeal constrictor muscles were contoured.

Predictive modeling of outcomes following definitive chemoradiotherapy for oropharyngeal cancer based on FDG-PET image characteristics.

In this study, we investigate the use of imaging feature-based outcomes research ('radiomics') combined with machine learning techniques to develop robust predictive models for the risk of all-cause mortality (ACM), local failure (LF), and distant metastasis (DM) following definitive chemoradiation therapy (CRT). One hundred seventy four patients with stage III-IV oropharyngeal cancer (OC) treated at our institution with CRT with retrievable pre- and post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans were identified. From pre-treatment PET scans, 24 representative imaging features of FDG-avid disease regions were extracted.

Genomic analysis of exceptional responders to radiotherapy reveals somatic mutations in ATM.

Radiation therapy is a mainstay of cancer treatment, yet the molecular determinants of clinical response are poorly understood. We identified exceptional responders to radiotherapy based on clinical response, and investigated the associated tumor sequencing data in order to identify additional patients with similar mutations. Among head and neck squamous cell cancer patients receiving palliative radiotherapy at our institution, we identified one patient with documented complete metabolic response.

Patterns of nodal failure after intensity modulated radiotherapy for nasopharyngeal carcinoma.

Objectives: To evaluate the sites of nodal failure (NF) of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT).

Study Design: Retrospective chart review.

Methods: We reviewed the records of 165 patients with nonmetastatic NPC treated with IMRT between July 1998 and April 2011 at our institution.

Long-term patterns of relapse and survival following definitive intensity-modulated radiotherapy for non-endemic nasopharyngeal carcinoma.

Background: We report treatment outcomes for a large non-endemic cohort of patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and chemotherapy.

Methods: We identified 177 consecutive patients with newly diagnosed, non-metastatic nasopharyngeal cancer treated with definitive IMRT between 1998 and 2011. Endpoints included local, regional, distant control, and overall survival.

Dose-volume factors correlating with trismus following chemoradiation for head and neck cancer.

Background: To investigate the dose-volume factors in mastication muscles that are implicated as possible causes of trismus in patients following treatment with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy for head and neck cancers.

Material And Methods: All evaluable patients treated at our institution between January 2004 and April 2009 with chemotherapy and IMRT for squamous cell cancers of the oropharynx, nasopharynx, hypopharynx or larynx were included in this analysis (N = 421). Trismus was assessed using CTCAE 4.