Breast Cancer Gene Mutations

By Priyanka Varma


Sept. 1st, 2022

Breast Cancer Gene panel testing have identified mutations in BRCA1 and BRCA2 to be the most common genetic cause in explaining positive family history of Breast cancer [1]. However, there are other mutations, like germline mutations in TP53 (tumor protein 53 gene), which is a tumor suppressor gene or the “The Guardian of the Genome”, located on chromosome 17p13.1, which also predispose to familial breast cancer. The gene has 11 exons, with a genomic length of 20 kb. Exons 2-11 are coding, while exon 1 is non-coding. Most of the variants are mis-sense variants with several mutational hotspots on codons atexons 5-8. The p53 protein is a cellular tumor antigen which functions as a checkpoint control, activating downstream genes to repair the damage or initiate apoptosis, following DNA damage. While an estimated frequency of breast cancer being due to TP53 germline mutations was estimated to be about 1in 17,000 to 1 in 23,000; in another study on 341 samples, the incidence of denovo TP53 mutations in early onset breast cancer was estimated to be anywhere between 7-20% [1, 2].

Fig 1: Breast Cancer Types Distribution

In another comprehensive analysis of the molecular portrait of breast cancer, it was noted that significantly mutated genes (SMG) were more diverse and recurrent in Luminal A and Luminal B mRNA expression subtypes than in Basal-like and HER-2 subtypes. Phosphatidylinositol 3-kinase catalytic subunit (PIK3CA) was the most SMG in Luminal A (45%), Luminal B (29%) subtypes; while TP53 was more frequent in basal-like (80%), HER2 (72%), and Luminal B(29%) subtypes. On the other hand, miRNA expression levels, assayed via Illumina sequencing were observed to have high overlap in groups 4 and 5 with basal-like mRNA subtype, containing many TP53 mutations with a strong positive correlation, and negative association of PIK3CA with groups 4 and 5. The other miRNA groups, (1-3, 6, 7) largely comprised of a mixture of Luminal-A,Lumina-B, and HER-2 positive tumors with little correlation with the subtypes[3].

ctDNA analysis is proposed to be an effective modality to detect subtype-specific breast cancer mutations, like, PIK3CA and TP53 and resistance genomic abnormalities like Estrogen Receptor 1 (ESR1) and erythroblastic leukemia viral oncogene homolog 2 (ERBB2) [4]. In a study conducted on a small sample (29) of early breast cancer patients, analyzing their plasma for ctDNA pre and post op through droplet digital PCR and Sanger Sequencing, PIK3CA mutation was identified in the tumor tissue in 15 patients as well as in their preoperative sample. However, 5 patients also showed the same mutation post-operatively [5].



1.      Schon K, Tischkowitz M. Clinical implications ofgermline mutations in breast cancer: TP53. Breast Cancer Res Treat. 2018Jan;167(2):417-423. doi: 10.1007/s10549-017-4531-y. Epub 2017 Oct 16. PMID:29039119; PMCID: PMC5790840.

2.      Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W,Malkin D, et al. High frequency of de novo mutations in Li–Fraumenisyndrome. J Med Genet. 2009;46(10):689–693.doi: 10.1136/jmg.2008.058958.

3.      Curtis C, et al. The Cancer Genome Atlasnetwork. Nature. 2012;490(7418):61–70. doi: 10.1038/nature11412.

4.      D’Amico P, Corvaja C, Gerratana L, Reduzzi C, Curigliano G, Cristofanilli M.The use of liquid biopsy in early breast cancer: clinical evidence and futureperspectives. J CancerMetastasis Treat 2021;7:3.

5.      Beaver JA, Jelovac D, Balukrishna S, et al.Detection of cancer DNA in plasma of early stage breast cancer patients. ClinCancer Res 2014;20:2643-50.

We use cookies to provide you with a greater online experience. By using our sites, you agree to our use of cookies. See our cookie policy.