Association analysis of germline variants in GEN1 with a susceptibility to prostate cancer in Polish men.

IF 2.8 4区医学 Q3 ONCOLOGY

Hereditary Cancer in Clinical Practice Pub Date : 2026-06-10 DOI:10.1186/s13053-026-00343-0

Katarzyna Gliniewicz, Klaudia Stempa, Dominika Wokołorczyk, Wojciech Kluźniak, Milena Kiljańczyk, Helena Rudnicka, Tomasz Huzarski, Jacek Gronwald, Jan Uciński, Tadeusz Dębniak, Marta Grabarczyk, Anna Jakubowska, Marek Szwiec, Marcin Lener, Jan Lubiński, Steven A Narod, Mohammad R Akbari, Cezary Cybulski

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引用次数: 0

Abstract

Background: The GEN1 gene is involved in DNA damage repair, as are several prostate cancer susceptibility genes, and is now included in several NGS clinical testing panels. The aim of our study was to investigate the role of GEN1 mutations in the etiology of prostate cancer.

Methods: First, we sequenced GEN1 in 390 Polish men with familial prostate cancer and 300 population controls using exome sequencing to identify protein-truncating variants and to analyze their possible association with prostate cancer risk. In addition, we performed a large association study of a recurrent frameshift variant of GEN1 (c.1929_1932delAAAG) among 5,857 men with unselected prostate cancer and 3,956 controls. We compared the clinical characteristics of prostate tumors in carriers of c.1929_1932delAAAG and in non-carriers. We conducted loss of heterozygosity (LOH) analysis at the GEN1 locus in prostate cancers from two men with the c.1929_1932delAAAG variant. To analyze survival, patients were followed from diagnosis to death for an average of 101 months.

Results: We detected two frameshift variants (c.2515_2519delAAGTT (p. Lys839Glufs*2), c.1539delT (p. Asp514Ilefs*13)) by sequencing the GEN1 gene of 390 Polish patients with familial prostate cancer and 300 cancer-free controls. Neither variant was associated with increased prostate cancer risk: c.2515_2519delAAGTT was detected in 20.5% of 390 cases and in 17.1% of 300 controls (p = 0.28), c.1539delT was detected in one case (0.3%) and none of the controls (p = 1.00). The GEN1 variant, c.1929_1932delAAAG (p. Lys645Cysfs*29), was observed in 13 of 5,857 (0.22%) unselected cases and 8 of 3,956 (0.20%) controls (OR = 1.10, p = 0.84). Clinical characteristics of prostate tumors in 13 carriers of c.1929_1932delAAAG and 5,844 non-carriers were similar. All-cause survival was similar for variant carriers and non-carriers (age-adjusted HR = 0.68, p = 0.76). The wild-type GEN1 allele was not lost in two prostate tumors in men with the c.1929_1932delAAAG variant.

Conclusions: Our analysis suggests that GEN1 is not a prostate cancer susceptibility gene. The study has clinical implications for genetic counseling of men who tested positive for germline variants of GEN1.

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波兰男性GEN1种系变异与前列腺癌易感性的关联分析

背景：GEN1基因与几个前列腺癌易感基因一样，参与DNA损伤修复，目前已被纳入多个NGS临床检测小组。我们研究的目的是探讨GEN1突变在前列腺癌病因学中的作用。方法：首先，我们对390名波兰家族性前列腺癌患者和300名人群对照进行了GEN1测序，利用外显子组测序来鉴定蛋白质截断变异，并分析它们与前列腺癌风险的可能关联。此外，我们在5857名未选择的前列腺癌患者和3956名对照患者中进行了GEN1复发移码变异（c.1929_1932delAAAG）的大型关联研究。我们比较了c.1929_1932delAAAG携带者和非携带者前列腺肿瘤的临床特征。我们对两名携带c.1929_1932delAAAG变异的男性前列腺癌的GEN1位点进行了杂合性缺失（LOH）分析。为了分析生存率，患者从诊断到死亡的平均随访时间为101个月。结果：通过对390例波兰家族性前列腺癌患者和300例无癌对照的GEN1基因测序，检测到两个移码变异(c.2515_2519delAAGTT (p. Lys839Glufs*2), c.1539delT （p. Asp514Ilefs*13）。这两种变异都与前列腺癌风险增加相关：390例病例中有20.5%检测到c.2515_2519delAAGTT， 300例对照中有17.1%检测到c.1539delT (p = 0.28)， 1例（0.3%）检测到c.1539delT，对照组中没有检测到c.1539delT （p = 1.00）。GEN1变异c.1929_1932delAAAG （p. Lys645Cysfs*29）在5857例未选择病例中的13例（0.22%）和3956例对照中的8例（0.20%）中被观察到（OR = 1.10, p = 0.84）。13例c.1929_1932delAAAG携带者与5844例非携带者前列腺肿瘤临床特征相似。变异携带者和非携带者的全因生存率相似（年龄校正HR = 0.68, p = 0.76）。在携带c.1929_1932delAAAG变异的两名男性前列腺肿瘤患者中，野生型GEN1等位基因并未丢失。结论：我们的分析表明GEN1不是前列腺癌的易感基因。该研究对GEN1种系变异检测呈阳性的男性进行遗传咨询具有临床意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Hereditary Cancer in Clinical Practice 医学-肿瘤学

CiteScore

3.10

自引率

5.90%

发文量

审稿时长

>12 weeks

期刊介绍： Hereditary Cancer in Clinical Practice is an open access journal that publishes articles of interest for the cancer genetics community and serves as a discussion forum for the development appropriate healthcare strategies. Cancer genetics encompasses a wide variety of disciplines and knowledge in the field is rapidly growing, especially as the amount of information linking genetic differences to inherited cancer predispositions continues expanding. With the increased knowledge of genetic variability and how this relates to cancer risk there is a growing demand not only to disseminate this information into clinical practice but also to enable competent debate concerning how such information is managed and what it implies for patient care. Topics covered by the journal include but are not limited to: Original research articles on any aspect of inherited predispositions to cancer. Reviews of inherited cancer predispositions. Application of molecular and cytogenetic analysis to clinical decision making. Clinical aspects of the management of hereditary cancers. Genetic counselling issues associated with cancer genetics. The role of registries in improving health care of patients with an inherited predisposition to cancer.