Abstract
Abstract
The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.
The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.
Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.
We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.
Publisher
Springer Science and Business Media LLC
Reference44 articles.
1. Pharoah PDP, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BAJ. Polygenic susceptibility to breast cancer and implications for prevention. Nature genetics 2002 31:1. Nat Publ Group; 2002;31:33–36.
2. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet. 1991;48:232–42.
3. Newman B, Austin MA, Lee M, King MC. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. PNAS Natl Acad Sci. 1988;85:3044–8.
4. Ghoussaini M, Pharoah PD. Polygenic susceptibility to breast cancer: current state-of-the-art. Future Oncol. 2009;5:689–701.
5. Group ABCS. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. British Journal of Cancer. Nat Publ Group; 2000;83:1301–1308.
Cited by
59 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献