尽管我们对遗传性癌症易感性的了解取得了重大进展，但已知的遗传性癌症易感综合征最多可以解释 20% 的早发性癌症。随着早发癌症患病率持续增加，需要评估人类基因组中以前无法进入的区域，利用基于三重或四重家族的架构进行变异过滤，可能会进一步揭示对癌症易感性的见解。为了评估比多基因组测序甚至短读长全基因组测序所能确定的更广泛的变异，我们采用了长读长全基因组测序，使用牛津纳米孔技术 (ONT) PromethION，包含 3 个家族，其中包含早期-使用三重或四重家族结构的发病癌症先证者。分析包括 2 个早发结直肠癌的三人家庭和一个由两个患有睾丸癌的兄弟姐妹组成的四人家庭，所有家庭的父母均未患病。确定每个个体的结构变异（SV）、表观遗传图谱和单核苷酸变异（SNV），并采用过滤策略根据家族结构对候选变异进行细化和优先排序。家族结构使我们能够专注于不适当的变异，同时过滤与未受影响的父母共享的变异，显着减少可能妨碍识别潜在疾病差异的背景变异。以这种方式鉴定了候选的从头变异和复合杂合变异。对一组三人在匹配的肿瘤和肿瘤前病变中的基因表达进行了评估。我们的研究证明了通过长读 ONT 全基因组测序对基因组变异进行简化分析的可行性，以及一种对关键变异进行优先排序以进一步评估致病性的方法，同时揭示了基于组的分析中可能缺失的内容。

Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidate d e novo and compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses.