Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A commentary on germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors

Genomic analysis is important for personalized medicine in cancer. Whole- or multi-gene analysis and molecular pathological analysis can provide valuable information for cancer therapy.

Breast cancer is one of the most common cancers in women [1]. Like other cancers, breast cancer is a diverse set of diseases, which can be divided into subtypes with different pathological and molecular characteristics. An understanding of the genes which predispose individuals to breast cancers is important for understanding the mechanisms of breast cancer development, and valuable for estimating the degree of malignancy and the prognosis of individual breast cancers. For example, triple-negative breast cancers (TNBCs), a group of breast cancers that are negative for estrogen receptors, progesterone receptors, and human epidermal growth factor receptor type 2—currently used therapeutic targets for breast cancer—also show pathological genomic heterogeneity. TNBCs account for about 5–19% of all breast cancers [1]. Although TNBCs are not homogeneous, this group of cancers lacks established treatments and therapeutic targets, such as endocrine therapy, and are primarily treated using general surgery and chemotherapy. Therefore, molecular analysis is required for elucidating the genetic predisposition for TNBCs. Such analysis will provide important information, which will form the basis for the identification of the character, prognosis, and treatment of cancers in this category.

BRCA1 and BRCA2 are well known to be genes, which predispose individuals to the development of breast cancer [2]. Other predisposing genes are almost certainly involved, but many have not yet been clearly identified. Changes in germline genes in breast cancer in various regional populations are therefore currently under investigation.

Hata et al. investigated the presence of pathogenic variants in germline in 583 Chinese women with breast cancer, using next-generation sequencing with a panel of 54 cancer-related genes [3]. Seventy-nine pathogenic variants were found in 21 cancer-related genes. The pathogenic variants identified accounted for 14.4% of the breast cancers. The most frequent genes with pathogenic variants were the BRCA1 and BRCA2 genes, followed by PALB2. Pathogenic variants of the BRCA1 gene were frequently found in TNBCs. In these TNBCs, pathogenic variants of PALB2, as well as BRCA1 were frequent, suggesting a strong association between these genes and breast cancer in the Chinese population [3].

PALB2 has also been linked to other cancers [4]. Studies have been conducted into therapies for patients with a pathogenic variant of PALB2. Because PALB2 is involved in DNA repair, as are BRCA1 and BRCA2, and disruption of genomic stability is considered to contribute to the risk of development of breast cancer [2], PARP inhibitors may also be effective in breast cancers with pathogenic PALB2 variants.

There have also been reports of the CHEK2 and ATM genes being associated with TNBCs in the European population [5, 6]. These variants either occurred at very low levels or were not found in the current analysis of a Chinese population. Various genomic factors have been found in regional populations in association studies. In order to find relevant factors in each population, it is necessary to perform analysis in each local population or ethnicity. It is important to continue to use multigene panels and comprehensive genomic analyses in each population.

Finding gene variants related to breast cancer may require sequencing of the entire gene, but not for specific variants. Variants found in the same causative gene for the same disease may vary from region to region, or ethnicity to ethnicity, and individual to individual as well [2, 7]. The pathogenic variants of the BRCA1 and BRCA2 genes that were found to be relevant in this work differ, for example, from those found in other European populations, and also show ethnic differences [3, 5, 6].

In such predisposition gene analysis, NGS-based gene set panel sequencing appears to be more effective than companion diagnosis for identifying single variants. Such analysis is often performed on a large scale, requiring the analysis of a large number of genes. It is therefore important to develop cost-effective panel analysis methods for large-scale analysis [8, 9].

In research published by Hata et al., an analysis of 583 Chinese patients with breast cancer suggested that PALB2 was associated with breast cancer, and particularly with a genetic predisposition to TNBCs. These researchers also suggested that the MUTYH gene, which has been reported to be associated with male breast cancer [10], may also be involved in female breast cancer. However, the number of patients these researchers examined was not sufficient to draw strong conclusion, and more extensive analysis will be needed to obtain stronger associations and insights into genes predisposing to each subtype.

In this paper the researchers reported the results of investigations into germline variants. Somatic mutation is also important in a tumor. In addition to analyzing germline mutations, analysis of somatic mutations in breast cancers may provide important insights into the biology of these diseases.

By integrating the results of previous publications, and performing research to clarify changes in cancer cells, it should be possible to determine the prognosis and effective treatment options for individual breast cancers now, and develop new targeted molecular therapies for breast cancer in the future. Such progress is essential for the realization of personalized medicine for breast cancer.


  1. 1.

    DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438–51.

    Article  Google Scholar 

  2. 2.

    Yadav S, Couch FJ. Germline genetic testing for breast cancer risk: the past, present, and future. Am Soc Clin Oncol Educ Book. 2019;39:61–74.

    Article  Google Scholar 

  3. 3.

    Hata C, Nakaoka H, Xiang Y, Wang D, Yang A, Liu D, et al. Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors. J Hum Genet. 2020.

  4. 4.

    Janssen B, Bellis S, Koller T, Tischkowitz M, Liau SS. A systematic review of predicted pathogenic PALB2 variants: an analysis of mutational overlap between epithelial cancers. J Hum Genet. 2020;65:199–205.

    Article  Google Scholar 

  5. 5.

    Weischer M, Bojesen SE, Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: metaanalyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008;26:542–8.

    Article  Google Scholar 

  6. 6.

    Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873–5.

    CAS  Article  Google Scholar 

  7. 7.

    Iso M, Suzuki M, Yanagi K, Minowa K, Sakurai Y, Nakano S, et al. The CFTR gene variants in Japanese children with idiopathic pancreatitis. Hum Genome Var. 2019;6:17.

    CAS  Article  Google Scholar 

  8. 8.

    Ahmadloo S, Nakaoka H, Hayano T, Hosomichi K, You H, Utsuno E, et al. Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2. J Hum Genet. 2017;62:561–7.

    CAS  Article  Google Scholar 

  9. 9.

    Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer. JAMA Oncol. 2019.

  10. 10.

    Rizzolo P, Silvestri V, Bucalo A, Zelli V, Valentini V, Catucci I, et al. Contribution of MUTYH variants to male breast cancer risk: results from a multicenter study in Italy. Front Oncol. 2018;8:583.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Tadashi Kaname.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kaname, T. A commentary on germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors. J Hum Genet 65, 589–590 (2020).

Download citation


Quick links