This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from August 1through August 15.

If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].

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Blood

Genetic Events Associated with Venetoclax Resistance in CLL Identified by Whole-Exome Sequencing of Patient Samples

Khalsa JK, Cha J, Naeem A, Murali I, Kuang Y, Vasquez K, Li L, Tyekucheva S, Fernandes SM, Sasi BK, Wang Z, Machado JH, Bai H, Alasfour M, Danysh BP, Slowik K, Jacobs RA, Davids MS, Paweletz CP, Leshchiner I, Getz G, Brown JR

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point. We found the previously described acquired BCL2-G101V mutation in only 4 of 11 patients, with 2 patients showing a very low variant allele fraction (0.03%-4.68%). Whole-exome sequencing revealed acquired loss(8p) in 4 of 11 patients, of which 2 patients also had gain (1q21.2-21.3) in the same cells affecting the MCL1 gene. In vitro experiments showed that CLL cells from the 4 patients with loss(8p) were more resistant to venetoclax than cells from those without it, with the cells from 2 patients also carrying gain (1q21.2-21.3) showing increased sensitivity to MCL1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to the combination of MCL1 inhibitor and venetoclax. Differential gene expression analysis comparing bulk RNA sequencing data from pretreatment and progression time points of all patients showed upregulation of proliferation, B-cell receptor (BCR), and NF-κB gene sets including MAPK genes. Cells from progression time points

Gastroenterology

Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma

Kumar S, Zhao J, Talluri S, Buon L, Mu S, Potluri LB, Liao C, Shi J, Chakraborty C, Gonzalez GB, Tai YT, Patel J, Pal J, Mashimo H, Samur MK, Munshi NC, Shammas MA

Background & Aims: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors.

Methods: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization.

Results: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process.

Conclusions: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

Journal of Clinical Oncology

Germline EGFR Mutations and Familial Lung Cancer

Oxnard GR, Chen R, Pharr JC, Koeller DR, Bertram AA, Dahlberg SE, Rainville I, Sholl LM, Jänne PA, Garber JE

Background: The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs).

Methods: The INHERIT study (NCT01754025) enrolled lung cancer patients whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in-person or remotely, providing germline testing and follow-up.

Results: 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon prior genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, consistent with a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver co-mutation. Among 36 germline carriers without a cancer diagnosis, 15 had CT imaging and 9 had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the Southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1 Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.

Conclusions: In this first prospective description of familial EGFR-mutant lung cancer, we identify a recent founder germline EGFR T790M variant enriched in the US Southeast. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.

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