Laura D. Wood

The genomic landscapes of human breast and colorectal cancers.

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

Somatic mutations in the notch, NF-KB, PIK3CA, and hedgehog pathways in human breast cancers

Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF‐KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved.

AB015. S015. Circulating tumor cells dynamics in pancreatic adenocarcinoma correlate with disease status: data from a prospective trial

Background: Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes in patients with pancreatic ductal adenocarcinoma (PDAC) correlate with disease-specific survival. Herein, we report results of a prospective observational trial on CTC dynamics to assess their clinical significance. Methods: The CLUSTER trial is a prospective longitudinal study on PDAC CTC dynamics (NCT02974764). Multiple peripheral blood samples are collected from 160 consecutively enrolled patients with PDAC diagnosis. CTCs are enriched using an isolation-by-size assay, and their phenotype is characterized by immunofluorescence. Results: Two major CTC subtypes are identified in all patients: epithelial CTCs (eCTCs) and mesenchymal CTCs (mCTCs). Patients who previously received neoadjuvant chemotherapy have significantly lower total CTCs (tCTCs) and mCTCs, compared to untreated patients eligible for upfront resection (P<0.001). In multivariable logistic regression analysis, preoperative numbers of tCTCs and mCTCs are the only predictors of early recurrence and disease-associated mortality, within 12 months from surgery (P=0.03). Surgical resection of the primary tumor results in significant reduction in CTC burden across all cell subtypes (P<0.001). Longitudinal monitoring of CTCs postoperatively shows an increase in CTC numbers within a median time of 2 months, prior to radiological evidence of disease recurrence. Conclusions: We report novel findings regarding CTCs from a large prospective trial in patients undergoing PDAC resection. CTC dynamics reflect response to treatment and progression of disease, providing important information on clinical outcomes, not available by current tumor markers and imaging.