Association between vascular ultrasound features and DNA sequencing in breast cancer: a preliminary study

Abstract

There are few radiogenomic studies to correlate ultrasound features of breast cancer with genomic changes. We investigated whether vascular ultrasound phenotypes are associated with breast cancer gene profiles for predicting angiogenesis and prognosis. We prospectively correlated quantitative and qualitative features of microvascular ultrasound (vascular index, vessel morphology, distribution, and penetrating vessel) and contrast-enhanced ultrasound (time-intensity curve parameters and enhancement pattern) with genomic characteristics in 31 breast cancers. DNA obtained from breast tumors and normal tissues were analyzed using targeted next-generation sequencing of 105 genes. The single-variant association test was used to identify correlations between vascular ultrasound features and genomic profiles. Chi-square analysis was used to detect single nucleotide polymorphisms (SNPs) associated with ultrasound features by estimating p values and odds ratios (ORs). Eight ultrasound features were significantly associated with 9 SNPs (p < 0.05). Among them, four ultrasound features were positively associated with 5 SNPs: high vascular index with rs1136201 in ERBB2 (p = 0.04, OR = 7.75); large area under the curve on contrast-enhanced ultrasound with rs35597368 in PDGFRA (p = 0.04, OR = 4.07); high peak intensity with rs35597368 in PDGFRA (p = 0.049, OR = 4.05) and rs2305948 in KDR (p = 0.04, OR = 5.10); and long mean transit time with rs2275237 in ARNT (p = 0.02, OR = 10.25) and rs755793 in FGFR2 (p = 0.02, OR = 10.25). We identified 198 non-silent SNPs in 71 various cancer-related genes. Vascular ultrasound features can reflect genomic changes associated with angiogenesis and prognosis in breast cancer.

Keywords: Biomarkers; Breast neoplasms; DNA; Prospective studies; Sequence analysis; Ultrasonography.

Fig. 1

Genomic landscape represented by angiogenesis and cancer-related genes in 31 breast cancer patients. A total of 198 non-silent (nonsynonymous) mutations in 71 genes were identified. The x column indicates 31 cancer patients, and the y column indicates the 71 genes with 198 non-silent mutations (small color bars except for green). PIK3CA showed the most frequent mutations in breast cancer genomes (16/31, 51.6%). Other recurrent non-silent mutations (≥ 3 cases) were found in 24 breast cancer- or cancer-related genes including TP53 (13 cases), ATM (7 cases), CDH1 (7 cases), APC (6 cases), ERBB2 (5 cases), FGFR1 (5 cases), and MET (5 cases)

Fig. 2

A 53-year-old female with invasive ductal carcinoma. a A microvascular US image shows an increased vascular index, 25.6% (above the mean value of 16.1%) (red box). b A contrast-enhanced US image shows high peak intensity, 67.4 × 10⁻⁵ AU (above the mean value of 34.2 × 10⁻⁵ AU), and area under the curve, 1916.1 × 10⁻⁵ AU·s (above the mean value of 890.0 × 10⁻⁵ AU·s), and low mean transit time, 13.9 s (below the mean value of 14.4 s). DNA sequencing results for the cancer showed the presence of SNP rs1136201 in ERBB2 gene, SNP rs2305948 in KDR gene, and SNP rs35597368 in PDGFRA gene. SNP, single nucleotide polymorphism

Fig. 3

A 49-year-old female with invasive ductal carcinoma. a A microvascular US image shows a low vascular index, 12.0% (below the mean value of 16.1%) (red box). b A contrast-enhanced US image shows low peak intensity, 17.9 × 10^− 5 AU (below the mean value of 34.2 × 10⁻⁵ AU), mean transit time, 6.4 s (below the mean value of 14.4 s), and area under the curve, 421.3 × 10^− 5 AU·s (below the mean value of 890.0 × 10^− 5 AU·s). DNA sequencing results for the cancer showed the absence of SNP rs1136201 in ERBB2, rs35597368 in PDGFRA, rs2305948 in KDR, rs2275237 in ARNT, and rs755793 in FGFR2. SNP, single nucleotide polymorphism

Fig. 4

Comparison of vascular US parameters according to the tumor size (≤ 20 mm vs. > 20 mm). a Microvascular US and contrast-enhanced US images of a 35 mm-sized invasive ductal carcinoma in a 47-year-old female show increased peak intensity, 46.2 × 10⁻⁵ AU (above the mean value of 34.2 × 10⁻⁵ AU), and area under the curve, 1875.6 × 10⁻⁵ AU·s (above the mean value of 890.0 × 10⁻⁵ AU·s). DNA sequencing results for the cancer showed the presence of rs35597368 in PDGFRA. b Microvascular US and contrast-enhanced US images of a 14 mm-sized invasive ductal carcinoma in a 62-year-old female show low peak intensity, 24.7 × 10⁻⁵ AU (below the mean value of 34.2 × 10⁻⁵ AU), and area under the curve, 787.5 × 10⁻⁵ AU·s (below the mean value of 890.0 × 10⁻⁵ AU·s). DNA sequencing results for the cancer showed the absence of rs35597368 in PDGFRA and rs2305948 in KDR. SNP, single nucleotide polymorphism