Distinct evolutionary trajectories of primary high grade serous ovarian cancers revealed through spatial mutational profiling

High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment-resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2 to 91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole-genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug-resistance mechanisms

高级浆液性卵巢癌（HGSC）以其不良预后为特征，其往往归因于治疗抵抗性亚克隆的出现。本研究旨在测量未经治疗的原始高级浆液性卵巢癌中基因组多样性的程度，以考察肿瘤在治疗前的自然演化状态。我们对31个空间和时间上分离的高级浆液性卵巢癌肿瘤样本（包括卵巢肿块、远处转移和输卵管病变）进行了外显子测序、拷贝数分析、靶向扩增子深度测序和基因表达谱分析。我们发现肿瘤内存在广泛的突变、拷贝数和基因表达谱的变异，关键驱动突变仅存在于部分样本中（例如PIK3CA、CTNNB1、NF1）。平均而言，每个病例的样本中只有51.5%的突变存在（范围从10.2%至91.4%），其中TP53是唯一在所有样本中持续存在的体细胞突变。在部分样本中，存在复杂的段性非整倍体，如全基因组倍增，这些非整倍体变化与点突变获得独立分离。演化历史的重建显示，一名患者同时存在混合型高级浆液性卵巢癌和子宫内膜样组织学类型，两者在输卵管中具有共同的病因起源，并在组织学上不同的样本中选择了不同的驱动突变。在这名患者中，我们观察到早期输卵管病变中存在混合细胞群体，这表明多样性起源于肿瘤发生早期阶段。我们的研究结果表明，高级浆液性卵巢癌在治疗前的演化轨迹高度个体化，基因组图谱多样化，揭示了未来个性化治疗方案设计和药物耐药机制研究的关键生物学特征。