Quantifying Y chromosome loss in primary and metastatic prostate cancer by chromosome painting.

Somatic Y chromosome loss in hematopoietic cells is associated with higher mortality in men. However, the status of the Y chromosome in cancer tissue is not fully known due to technical limitations, such as difficulties in labelling and sequencing DNA from the Y chromosome. We have developed a system to quantify Y chromosome gain or loss in patient-derived prostate cancer organoids.

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer.

Purpose: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance.

Experimental Design: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT).

Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer.

Unlabelled: With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression.

Error-prone repair of stalled replication forks drives mutagenesis and loss of heterozygosity in haploinsufficient BRCA1 cells.

Germline mutations in the BRCA genes are associated with a higher risk of carcinogenesis, which is linked to an increased mutation rate and loss of the second unaffected BRCA allele (loss of heterozygosity, LOH). However, the mechanisms triggering mutagenesis are not clearly understood. The BRCA genes contain high numbers of repetitive DNA sequences.

Ordered and deterministic cancer genome evolution after p53 loss.

Although p53 inactivation promotes genomic instability and presents a route to malignancy for more than half of all human cancers, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases-Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications-each associated with specific histological stages across the premalignant and malignant spectrum.