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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. The development of DNA repair deficiency biomarkers is critical to the implementation of therapeutic targeting of repair-deficient tumors, using either DNA damaging agents or immunotherapy for the personalization of cancer therapy. Targeting DNA repair-deficient tumors is one of the most promising therapeutic strategies in cancer research; however, accurately predicting which tumors will respond can be a challenge. Here the authors present a review of the current state of knowledge in DNA repair deficiency across human cancers.

Treatment of oropharyngeal squamous cell carcinoma with chemoradiotherapy can now accomplish excellent locoregional disease control, but patient overall survival (OS) remains limited by development of distant metastases (DM). We investigated the prognostic value of staging (18)F-FDG PET/CT, beyond clinical risk factors, for predicting DM and OS in 176 patients after definitive chemoradiotherapy. The PET parameters maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were recorded. Univariate Cox regression was used to examine the prognostic value of these variables and clinical prognosticators for local treatment failure (LTF), OS, and DM. Multivariate analysis examined the effect of SUVmax, TLG, and MTV in the presence of other covariates. Kaplan-Meier curves were used to evaluate prognostic values of PET/CT parameters. Primary tumors were distributed across all stages. Most patients underwent chemoradiotherapy only, and 11 also underwent tonsillectomy. On univariate analysis, primary tumor MTV was predictive of LTF (P = 0.005, hazard ratio [HR] = 2.4 for a doubling of MTV), DM and OS (P < 0.001 for both, HR = 1.9 and 1.8, respectively). The primary tumor TLG was associated with DM and OS (P < 0.001, HR = 1.6 and 1.7, respectively, for a doubling of TLG). The primary tumor SUVmax was associated with death (P = 0.029, HR = 1.1 for a 1-unit increase in standardized uptake value) but had no relationship with LTF or DM. In multivariate analysis, TLG and MTV remained associated with death after correcting for T stage (P = 0.0125 and 0.0324, respectively) whereas no relationship was seen between standardized uptake value and death after adjusting for T stage (P = 0.158). Parameters capturing the volume of (18)F-FDG-positive disease (MTV or TLG) provide important prognostic information in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy and should be considered for risk stratification in this disease.

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.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.

Background Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation . The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear. Methods We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher’s exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations. Results We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls ( n  = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A , which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2 . Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A . Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation. Conclusions This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

BackgroundMutations 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 (ATM) 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 ATM loss on tumor immunogenicity are poorly understood.MethodsWe generated isogenic ATM-null models using CRISPR in murine triple-negative breast (4T1) and colorectal (CT26) cancer cell lines. ATM inactivation was confirmed by PCR and western blot. Immune cell infiltrates were assessed by flow cytometry and immunohistochemistry in both murine tumors and human samples from breast and lung cancers (via The Cancer Genome Atlas and institutional cohorts). In vivo, the impact of ATM loss on tumor growth and response to immune checkpoint blockade (anti-programmed cell death protein-1 (PD-1)) was evaluated. Furthermore, we compared the effects of different DNA-damaging agents—including an ATR inhibitor (RP-3500), a PARP inhibitor (olaparib), and the topoisomerase II inhibitor etoposide—on interferon-stimulated gene (ISG) expression and immune modulation.ResultsWe find that—in contrast to other DNA repair defects—ATM deficiency (1) fails to encourage immune effector cell infiltration into tumors, and (2) does not enable immune cell recruitment via synthetic lethality strategies in clinical trials, such as with ATR inhibition. Assessing various DNA-damaging agents in Atm null tumors revealed a differential activation of type I interferon (IFN) signaling, with etoposide, a topoisomerase II inhibitor, emerging as the strongest activator of ISG under these conditions. Yet, PD-1-targeted immune checkpoint blockade does not bolster the therapeutic activity of etoposide in Atm-null syngeneic tumor models, nor does it modify the tumor microenvironment, suggesting that type I IFN signaling alone is insufficient to overcome immunosuppression in immunologically cold ATM null neoplasms.ConclusionsATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for ATM null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair.

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 (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations 1 . Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure 2 . 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. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one ( cis ) outcome corresponded to the copying and pasting of a small segment to a distant site, a second ( trans ) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells. Linked-read whole-genome sequencing reveals patterns of structural DNA variants that are specific to homologous recombination deficiency and can be used to distinguish between BRCA1- and BRCA2-deficient phenotypes.

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. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure. JaBbA v1 pinpoints the ‘loose ends’ of large (>10-kb) unmapped structural variants in short-read DNA sequencing, suggesting that about 90% of cancer chromosomal alterations outside centromeres are resolvable with short reads and that long reads will primarily improve calling of smaller somatic variants.

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. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

Purpose Regional failure rates are low in patients with a positive sentinel lymph node biopsy (SLNB) who undergo breast-conserving therapy without axillary lymph node dissection (ALND). The applicability of these findings to total mastectomy (TM) patients is not established. Our aims were to evaluate the characteristics and outcomes of SLNB-positive TM patients who did not receive axillary-specific treatment and to compare them to similar patients who underwent breast-conserving surgery (BCS). Methods A total of 535 patients with early-stage breast cancer who underwent definitive breast surgery (210 TM, 325 BCS), had a positive SLNB and did not receive ALND between 1997 and 2009 were identified from an institutional database. Characteristics and outcomes were compared between the TM and BCS groups. Results Most patients had stage I to IIA, estrogen receptor–positive, progesterone receptor–positive, Her2-negative invasive ductal carcinoma, with minimal nodal disease. Compared to the BCS group, TM patients were younger, had larger tumors, had higher nomogram scores predicting additional axillary disease and were more likely to receive chemotherapy. Ninety-four percent of the BCS cohort and 5 % of the TM cohort received adjuvant radiotherapy. At a median follow-up of 57.8 months, the 4-year local, regional and distant failure rates were 1.7, 1.2 and 0.7 % in the TM group and 1.4, 1.0 and 3.7 % in the BCS group. The 4-year disease-free and overall survival rates were 94.8 and 97.8 % in the TM group and 90.1 and 92.6 % in the BCS group. Conclusions Early-stage breast cancer patients with minimal sentinel node disease experience excellent outcomes without ALND, whether they undergo BCS or TM.