Acquired mutations are pervasive across normal tissues. However, our understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMN). We find mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response (DDR) genes ( TP53, PPM1D, CHEK2 ). Sequential sampling provides definitive evidence that DDR clones outcompete other clones when exposed to certain therapies. Among cases where CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

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In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICI). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types, before/without ICI treatment, or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients, in whom higher TMB was associated with longer survival.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic 90 therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and genetreatment interactions. We validate these associations in serial sampling from 525 patients and 95show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapyrelated myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions. 100

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.

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