Hereditary Cancer Programme, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.
Oncobell Programme, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
J Med Genet. 2023 Nov;60(11):1035-1043. doi: 10.1136/jmg-2022-108984. Epub 2023 Apr 19.
While constitutional pathogenic variants in the gene cause familial adenomatous polyposis, c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.
虽然基因中的致病性变异会导致家族性腺瘤性息肉病，但 c.3920T>A;p.Ile1307Lys（I1307K）与结直肠癌（CRC）的中度风险增加相关，尤其是在阿什肯纳兹犹太人后裔中。然而，已发表的数据包括相对较小的样本量，导致关于癌症风险的结果不确定，特别是在非阿什肯纳兹人群中。这导致不同国家/大陆特定的基因检测、临床管理和监测建议指南不同，针对 I1307K。一个由国际胃肠道遗传肿瘤学会（InSiGHT）认可的多学科国际专家小组就 I1307K 等位基因及其与癌症易感性的关联发表了一份立场声明。基于对已发表证据的系统评价和荟萃分析，本文件旨在总结 I1307K 等位基因的流行率，并分析不同人群中与癌症风险相关的证据。在这里，我们提供了关于该变体的实验室分类建议，定义了对 I1307K 进行预测性检测的作用，提出了针对 I1307K 杂合子和纯合子个体的癌症筛查建议，并确定了未来研究中需要解决的知识空白。简而言之，I1307K 被归类为致病性、低外显率，是阿什肯纳兹犹太人起源个体 CRC 的风险因素，应在该人群中进行检测，为携带者提供特定的临床监测。没有足够的证据表明其他人群/亚人群存在癌症风险增加。因此，除非未来有证据表明情况有所不同，否则携带 I1307K 的非阿什肯纳兹犹太血统个体应被纳入针对一般风险个体的国家 CRC 筛查计划。
