Down's Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship

Abstract

Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient's tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease.

Keywords: Down’s syndrome; PI3K-mTOR pathway; triple negative breast cancer; tumor suppressor genes.

Figure 1

Comprehensive genomic profile of the patient from FoundationOne and Guardant360 data is presented. Genomic alterations identified from FoundationOne data showed a frameshift mutation of INPP4B and TP53. VUS (variance of unknown significance) are shown in rows in gray. The Guardant360 Table shows the mutant allele percentage (% cfDNA) of observed somatic variants at the basal level (sample submission time point). The “Somatic Alteration Burden” value below refers to the maximum % cfDNA detected at the basal time point. The Guardant360 presents a summary of somatic alterations. The percentage of altered cell-free DNA (% cfDNA) circulating in the blood is measured. The table annotates the allele frequency of altered circulating cell-free DNA (% cfDNA) detected in the patient. Alterations are listed in descending order of % cfDNA by the gene.

Figure 2

Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor. VUS genes (Figure 1: in gray shade) from the FoundationOne results show that RUNX1 and ERG genes are amplified in the patient’s tumor.

Figure 3

Photomicrograph of H&E stained invasive breast carcinoma (magnification ×40 and magnification ×200): The tumor is composed of large irregular to rounded nests of cells with pleomorphic nuclei and hyperchromasia. Mitoses and dense lymphoplasmacytic infiltration are observed.

Figure 4

PET/CT of the tumor before (left panel) and after (right panel) the treatment. The right panel shows no evidence of tumor.

Figure 5

Domain structure, function, and signaling of INPP4B.