Cancer drivers converge on NOTCH Cancer genome–sequencing projects have emphasized the handful of genes mutated at high frequency in patients. Less attention has been directed to the hundreds of genes mutated in only a few patients—the so-called “long tail” mutations. Although rare, these mutations may nonetheless inform patient care. Loganathan et al. developed a reverse genetic CRISPR screen that allowed them to functionally assess in mice nearly 500 long tail gene mutations that occur in human head and neck squamous cell carcinoma (HNSCC). They identified 15 tumor-suppressor genes with activities that converged on the NOTCH signaling pathway. Given that NOTCH itself is mutated at high frequency in HNSCC, these results suggest that the growth of these tumors is largely driven by NOTCH inactivation. Science, this issue p. 1264 Functional analysis of rare mutations in head and neck cancers reveals that NOTCH signaling is disrupted in most tumors. In most human cancers, only a few genes are mutated at high frequencies; most are mutated at low frequencies. The functional consequences of these recurrent but infrequent “long tail” mutations are often unknown. We focused on 484 long tail genes in head and neck squamous cell carcinoma (HNSCC) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. Our results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.

中文翻译：

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头颈部鳞状细胞癌中罕见的驱动突变集中在 NOTCH 信号上

癌症驱动因素集中在 NOTCH 癌症基因组测序项目强调了患者体内少数高频突变的基因。很少有人关注仅在少数患者中发生的数百个基因突变——所谓的“长尾”突变。尽管很少见，但这些突变可能会为患者护理提供信息。洛加纳森等人。开发了一种反向遗传 CRISPR 筛选，使他们能够在小鼠中对人类头颈部鳞状细胞癌 (HNSCC) 中发生的近 500 个长尾基因突变进行功能评估。他们鉴定了 15 个肿瘤抑制基因，其活性集中在 NOTCH 信号通路上。鉴于 NOTCH 本身在 HNSCC 中发生高频突变，这些结果表明这些肿瘤的生长主要是由 NOTCH 失活驱动的。科学，这个问题 p。1264 头颈癌罕见突变的功能分析表明，大多数肿瘤中的 NOTCH 信号传导被破坏。在大多数人类癌症中，只有少数基因发生高频率突变；大多数在低频发生突变。这些反复出现但不常见的“长尾”突变的功能后果通常是未知的。我们专注于头颈部鳞状细胞癌 (HNSCC) 中的 484 个长尾基因，并使用体内 CRISPR 来筛选突变时触发小鼠肿瘤发展的基因。在鉴定的 15 个肿瘤抑制基因中，ADAM10 和 AJUBA 通过促进 NOTCH 受体信号传导以单倍不足的方式抑制 HNSCC。ADAM10 和 AJUBA 突变或单等位基因丢失发生在 28% 的人类 HNSCC 病例中，并且与 NOTCH 受体突变相互排斥。