Biology subjects

Perdigones, N.

Publications and source records attributed to Perdigones, N..

3 recordsLinked to original sources

bioRxiv2020

Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients

Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancers clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within individual patients cancers can limit the power of mutations to serve as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within patients in canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 44 dogs (28 HSA, 15 benign masses, and 1 stromal sarcoma) presenting to emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal cancer gene panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/28 (50%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (29%) followed by PIK3CA (14%), AKT1 (11%), and CDKN2AIP (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspective on the genomic landscape and comparative value of understanding HSA in pet dogs, particularly as a naturally occurring cancer bearing intratumoral heterogeneity.

cancer biology↗

bioRxiv2019

Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Naturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 88 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 38% of canine pulmonary adenocarcinomas (cPAC, 28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, PTEN was the most frequently mutated gene (18%) while one case each bore likely pathogenic HRAS, KRAS, EGFR, MET, TP53, or VHL somatic mutations. In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (13.5%), SMAD4 (5.4%), PTEN (4.1%), and VHL (2.7%). cPACs assessed by exome sequencing displayed a low somatic mutation burden (median 64 point mutations, 19 focal copy number variants, and 1 translocation). The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E correlated with constitutive phosphorylation of AKT in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines. These findings have translational and comparative relevance for lung cancer and HER2 inhibition.

cancer biology↗

bioRxiv2018

Detection of residual disease after neoadjuvant therapy in breast cancer using personalized circulating tumor DNA analysis

Accurate detection of minimal residual disease (MRD) can guide individualized management of early stage cancer patients, but current diagnostic approaches lack adequate sensitivity. Circulating tumor DNA (ctDNA) analysis has shown promise for recurrence monitoring but MRD detection immediately after neoadjuvant therapy or surgical resection has remained challenging. We have developed TARgeted DIgital Sequencing (TARDIS) to simultaneously analyze multiple patient-specific cancer mutations in plasma and improve sensitivity for minute quantities of residual tumor DNA. In 77 reference samples at 0.03%-1% mutant allele fraction (AF), we observed 93.5% sensitivity. Using TARDIS, we analyzed ctDNA in 34 samples from 13 patients with stage II/III breast cancer treated with neoadjuvant therapy. Prior to treatment, we detected ctDNA in 12/12 patients at 0.002%-1.04% AF (0.040% median). After completion of neoadjuvant therapy, we detected ctDNA in 7/8 patients with residual disease observed at surgery and in 1/5 patients with pathological complete response (odds ratio, 18.5, Fishers exact p=0.032). These results demonstrate high accuracy for a personalized blood test to detect residual disease after neoadjuvant therapy. With additional clinical validation, TARDIS could identify patients with molecular complete response after neoadjuvant therapy who may be candidates for nonoperative management.\n\nOne Sentence SummaryA personalized ctDNA test achieves high accuracy for residual disease.

genomics↗