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Infection with Helicobacter pylori is known to confer a risk of gastric cancer. In this study, persons who carried certain genetic variants and were infected with H. pylori had an excess risk of gastric cancer.

Immune-checkpoint inhibitors show promising effects in the treatment of multiple tumor types. Biomarkers are biological indicators used to select patients for a systemic anticancer treatment, but there are only a few clinically useful biomarkers such as PD-L1 expression and tumor mutational burden, which can be used to predict immunotherapy response. In this study, we established a database consisting of both gene expression and clinical data to identify biomarkers of response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 immunotherapies. A GEO screening was executed to identify datasets with simultaneously available clinical response and transcriptomic data regardless of cancer type. The screening was restricted to the studies involving administration of anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab) or anti-CTLA-4 (ipilimumab) agents. Receiver operating characteristic (ROC) analysis and Mann-Whitney test were executed across all genes to identify features related to therapy response. The database consisted of 1434 tumor tissue samples from 19 datasets with esophageal, gastric, head and neck, lung, and urothelial cancers, plus melanoma. The strongest druggable gene candidates linked to anti-PD-1 resistance were SPIN1 (AUC = 0.682, P  = 9.1E-12), SRC (AUC = 0.667, P  = 5.9E-10), SETD7 (AUC = 0.663, P  = 1.0E-09), FGFR3 (AUC = 0.657, P  = 3.7E-09), YAP1 (AUC = 0.655, P  = 6.0E-09), TEAD3 (AUC = 0.649, P  = 4.1E-08) and BCL2 (AUC = 0.634, P  = 9.7E-08). In the anti-CTLA-4 treatment cohort, BLCAP (AUC = 0.735, P  = 2.1E-06) was the most promising gene candidate. No therapeutically relevant target was found to be predictive in the anti-PD-L1 cohort. In the anti-PD-1 group, we were able to confirm the significant correlation with survival for the mismatch-repair genes MLH1 and MSH6 . A web platform for further analysis and validation of new biomarker candidates was set up and available at https://www.rocplot.com/immune . In summary, a database and a web platform were established to investigate biomarkers of immunotherapy response in a large cohort of solid tumor samples. Our results could help to identify new patient cohorts eligible for immunotherapy.

IntroductionThe incidence of early-onset colorectal cancer (EoCRC), diagnosed before age 50, has increased over the past 10-20 years. This abstract describes the demographics, route to diagnosis and staging in a group of patients with EoCRC and compares them with a group of patients with average-onset CRC (AoCRC).MethodThe Northumbria Colorectal Cancer Database (NCCD) is a prospectively maintained database of all colorectal cancer cases diagnosed in Northumbria. All patients below age 50 at diagnosis between 2010-2024 were included in the EoCRC cohort. A comparator group diagnosed at age 50 and over between 2023 and 2024 were selected. Patient demographics (age, gender, BMI), route of referral, Duke stage, FiT test and status of genetic assessment were analysed. Unpaired t-tests and Chi-squared tests were used to determine if there was a significant difference between cohorts.ResultsThere were 210 patients with EoCRC identified in a 14 year period (out of 4707 colorectal cancer patients in all ages (4.5%)). Mean age in the EoCRC group was 43 years (range 19-49 years) compared to 73 years (range 50-95 years) in the AoCRC group. Characteristics of the two groups are shown in the table 1.Abstract P308 Table 1 EoCRC (n=210) AoCRC (n=342) p-value Male 114 (54%) 186 (54%) 0.98 Female 96 (46%) 156 (46%) GP referral 130 (61.9%) 222 (64.9%) <0.05 Emergency admission 54 (25.7%) 45 (13.2%) Referred from BCSP 0 58 (17%) Unknown/Other route of presentation 26 (12.4%) 17 (5%) Rectal 86 (41%) 108 (31.6%) <0.05 Right colon 67 (32%) 96 (28.1%) Left colon 57 (27%) 138 (40.4%) Duke Stage A+B 61 (29%) 134 (39%) <0.05 Duke Stage C+D 121 (57.6%) 127 (37%) FiT tests performed (from 2019 onwards) 24/62 (38.7%) 228 (66.7%) FIT value <10 µg/g 1 (4%) 1 (0.4%) 0.95 FIT value >10 µg/g (value not recorded) 5 (20.8%) 41 (17.4%) FIT value 10-100 µg/g 4 (16.7%) 47 (20%) FIT value >100 µg/g 14 (58.3%) 139 (59.2%) MSI testing performed (from 2016 onwards) 112/141 (79.4%) 280 (82%) MSI stable 105 (93.8%) 239 (85.4%) <0.05 MSI instability 7 (6.2%) 41 (14.6%) MMR mutation 5 (PMS 3, MSH6 2) 4 (MLH1 3, MSH6 1) ConclusionEarly onset CRC has different characteristics to average onset CRC. In a cohort from Northumbria, patients with EoCRC were more likely to present as an emergency, were more likely to have advanced stage disease at diagnosis and were more likely to have cancer located in the rectum. Of 24 cases with EoCRC presenting following a FIT test, 5 had a FIT <100µg/g. Further work to clarify the role of FIT testing in patients under 50 with lower GI symptoms is needed.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Prime editing (PE) is a powerful genome engineering approach that enables the introduction of base substitutions, insertions and deletions into any given genomic locus. However, the efficiency of PE varies widely and depends not only on the genomic region targeted, but also on the genetic background of the edited cell. Here, to determine which cellular factors affect PE efficiency, we carry out a focused genetic screen targeting 32 DNA repair factors, spanning all reported repair pathways. We show that, depending on cell line and type of edit, ablation of mismatch repair (MMR) affords a 2–17 fold increase in PE efficiency, across several human cell lines, types of edits and genomic loci. The accumulation of the key MMR factors MLH1 and MSH2 at PE sites argues for direct involvement of MMR in PE control. Our results shed new light on the mechanism of PE and suggest how its efficiency might be optimised. Prime Editing is a versatile genome engineering tool. Here, the authors identify the DNA repair pathway known as mismatch repair as inhibitory for Prime Editing, thus, loss of mismatch repair enhances the efficiency of Prime Editing.

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair–deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.

The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.Activation of TP53 can stimulate diverse cellular responses. In unstressed cells, the TP53 protein is bound and ubiquitinated by its negative regulator, the E3 ubiquitin ligase MDM2 (called HDM2 in humans). This targets the TP53 protein for ubiquitin-dependent proteasomal degradation. When cells are exposed to stress, such as DNA damage, MDM2 is phosphorylated and is then no longer able to ubiquitinate TP53, allowing for TP53 stabilisation and functional activation. Of note, TP53 can be phosphorylated at the N-terminus, and this also interferes with MDM2 binding and its ability to ubiquitinate TP53, and thereby prime it for proteasomal degradation. Once activated, TP53 can transcriptionally induce ~500 direct target genes, with some of them known to be critical for the induction of diverse cellular responses, including apoptotic cell death via induction of PUMA and NOXA, as well as genes involved in cell cycle arrest and cell senescence, (e.g., p21), DNA repair (e.g., MLH1, MSH2) and metabolism (e.g., TIGAR), to implement tumour suppression.

Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma–carcinoma sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9–12·6), and median follow-up from diagnosis was 7·2 years (3·6–14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80–99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8–3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30–52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55–82]), gastrointestinal cancers (89% [81–97]), and other solid tumours (96% [88–100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55–73] for PMS2, 49% [35–68] for MSH6, 19% [6–66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. Pfizer/Medivation.