具有高癌症风险、化疗毒性、染色体脆性和性腺功能衰竭的隐性FANCM癌症综合征。

Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure.

作者信息

Nynäs Erja, Sulkava Sonja, Nurmi Anna K, Suvanto Maija, Aittomäki Kristiina, Nevanlinna Heli

机构信息

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; SleepWell Research Programme, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

出版信息

Genet Med. 2025 Jul 7;27(10):101521. doi: 10.1016/j.gim.2025.101521.

DOI:10.1016/j.gim.2025.101521

PMID:40642874

Abstract

PURPOSE

Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking.

METHODS

We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals.

RESULTS

Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 × 10) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 × 10), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA.

CONCLUSION

Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.

摘要

目的

杂合型FANCM变异与乳腺癌相关。仅有少数研究考察了其他癌症类型。在病例报告中，双等位基因截短变异与一种范可尼贫血（FA）样癌症易感综合征有关；然而，癌症范围和风险估计尚缺乏。

方法

我们在芬兰基因数据中对500348名个体研究了芬兰富集变异c.5101C>T p.(Gln1701Ter)和c.5791C>T p.(Arg1931Ter)与任何癌症风险及FA相关病症的关联。

结果

杂合型c.5101C>T（N = 10940）不仅与乳腺癌风险增加相关（比值比 = 1.24，P = 2.7×10），还与其他癌症类型风险相关，包括下咽癌（比值比 = 3.98，P = 3.6×10）【此处原文P值有误，推测可能是10的负几次方的形式】，提示风险效应比之前描述的更广泛。纯合型c.5101C>T（N = 76）与乳腺癌、头颈癌、胃肠道癌、妇科癌、血液系统癌、皮肤癌和肺癌的高风险相关，而c.5791C>T罕见。此外，检测到癌症治疗后卵巢功能障碍和血液学副作用的高隐性风险，但未发现骨髓衰竭风险或FA的身体特征。