Sukrithan Vineeth, Boateng Isaiah, Liyanarachchi Sandya, Jain Prachi, Buss Jill, Parwani Anil, Shah Manisha H, Das Komal, Yearsley Martha, Konda Bhavana, Brock Pamela, Eisfeld Ann-Kathrin
1The Ohio State University, Columbus, OH.
J Natl Compr Canc Netw. 2025 Jun 30;23(9):379-384. doi: 10.6004/jnccn.2025.7035.
Beyond syndromic tumor-predisposing conditions, germline susceptibility to neuroendocrine neoplasms (NENs) is not well understood. Familial clustering of cases and the co-occurrence of additional malignancies in patients suggest that additional, thus far unrecognized, germline predispositions to NEN development may exist.
We conducted whole-exome sequencing of germline and somatic DNA from a prospective cohort of patients with NENs (n=144) treated at The Ohio State University. Gene ontology analysis was performed using the DAVID algorithm. Multiplex immunofluorescence (mIF) was conducted on samples with germline MUTYH (gMUTYH) alterations. Clinical data from patients with gMUTYH alterations who were treated with immune checkpoint inhibition (ICI) were also abstracted.
A total of 144 samples were sequenced, revealing 3,400 variants, including 75 pathogenic and 99 likely pathogenic. Pathogenic/likely pathogenic variants were found in 78% of patients (112/144), across 127 genes. Pathogenic variants alone were identified in 45% (65/144), across 57 genes. Recurrent alterations were detected in 37 genes (frequency, false discovery rate), including MEN1 (5%; 1.22E-17), MUTYH (5%; 0.003), PKD1 (5%; 0.003), ATP4A (4%; 0.04), and PAH (4%; 0.003). The 3 most commonly involved pathways were DNA repair (26%), cellular calcium signaling (14%), and epigenetic regulation (7%). gMUTYH alterations were associated with high somatic tumor mutational burden in 3 of 6 patients. Among 5 subjects with gMUTYH, 2 showed a high levels of CD3+ and CD11c+ immune infiltration on mIF. Separately, we reported 2 cases of gMUTYH-altered NENs with robust responses to ICI.
Approximately 45% of patients with NENs harbor pathogenic germline variants on whole-exome sequencing. A subset of patients with gMUTYH alterations demonstrate a high tumor mutational burden, rich immune infiltration, and significant responses to ICI.
除了综合征性肿瘤易感情况外，对于种系对神经内分泌肿瘤（NENs）的易感性了解尚少。病例的家族聚集性以及患者中其他恶性肿瘤的共同出现表明，可能存在迄今未被认识的、额外的种系对NEN发生的易感性。
我们对俄亥俄州立大学治疗的一组前瞻性NEN患者（n = 144）的种系和体细胞DNA进行了全外显子组测序。使用DAVID算法进行基因本体分析。对有种系MUTYH（gMUTYH）改变的样本进行多重免疫荧光（mIF）检测。还提取了接受免疫检查点抑制（ICI）治疗的gMUTYH改变患者的临床数据。
共对144个样本进行了测序，发现3400个变异，包括75个致病性变异和99个可能致病性变异。在78%的患者（112/144）中发现了致病性/可能致病性变异，分布在127个基因中。仅致病性变异在45%（65/144）的患者中被鉴定出，分布在57个基因中。在37个基因中检测到复发性改变（频率，错误发现率），包括MEN1（5%；1.22E - 17）、MUTYH（5%；0.003）、PKD1（5%；0.003）、ATP4A（4%；0.04）和PAH（4%；0.003）。3个最常涉及的途径是DNA修复（26%）、细胞钙信号传导（14%）和表观遗传调控（7%）。6例患者中有3例gMUTYH改变与高体细胞肿瘤突变负担相关。在5例gMUTYH改变的受试者中，2例在mIF上显示高水平的CD3 + 和CD11c + 免疫浸润。另外，我们报告了2例gMUTYH改变的NENs对ICI有显著反应的病例。
在全外显子组测序中，约45%的NEN患者携带致病性种系变异。一部分gMUTYH改变的患者表现出高肿瘤突变负担、丰富的免疫浸润以及对ICI的显著反应。
