Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities.

OBJECTIVES: The advent of germline testing as a standard-of-care practice for certain tumor types and patients presents unique opportunities and challenges for the field of precision oncology. This article describes strategies to address workforce capacity, organizational structure, and genetics education needs within the US Department of Veterans Affairs (VA) with the expectation that these approaches may be applicable to other health care systems. OBSERVATIONS: Germline information can have health, reproductive, and psychosocial implications for veterans and their family members, which can pose challenges when delivering germline information in the setting of cancer care. Additional challenges include the complexity inherent in the interpretation of germline information, the national shortage of genetics professionals, limited awareness and knowledge about genetic principles among many clinicians, and organizational barriers, such as the inability to order genetic tests and receive results in the electronic health record. These challenges demand thoughtful implementation planning at the health care system level to develop sustainable strategies for the delivery of high-quality genetic services in precision oncology practice. CONCLUSIONS: The VA is uniquely positioned to address the integration of germline genetic testing into precision oncology practice due to its outsized role in treating veterans with cancer, training the health care workforce, and developing, testing, and implementing innovative models of clinical care.

A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers.

While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.

HPLC-ESI-MS/MS analysis of hemoglobin peptides in tryptic digests of dried-blood spot extracts detects HbS, HbC, HbD, HbE, HbO-Arab, and HbG-Philadelphia mutations.

BACKGROUND: Hemoglobinopathies are mutations resulting in abnormal globin chain structure; some have clinically significant outcomes such as anemia or reduced lifespan. Five ß-globin mutations are (c.20A>T, p.E6V), (c.19G>A, p. E6K), (c.79G>A, p.E26K), (c.364G>C, p.E121Q), and (c.364G>A, p.E121K), resulting in HbS (sickle-cell hemoglobin), HbC, HbE, HbD-Los Angeles, and HbO-Arab, respectively. One α-globin mutation is (c.[207C>G or 207C>A], p.N68K), resulting in HbG-Philadelphia. METHODS: HPLC-ESI-MS/MS analysis of dried-blood spot (DBS) punches from newborns extracted with a trypsin-containing solution provides greater than 90% coverage of α-, ß-, and γ-globin amino acid sequences. Because the (c.20A>T, p.E6V), (c.19G>A, p. E6K), (c.79G>A, p.E26K), (c.364G>C, p.E121Q), (c.364G>A, p.E121K), and (c.[207C>G or 207C>A], p.N68K) mutations generate globin peptides with novel amino acid sequences, detecting one of these peptides in DBS extracts is indicative of the presence of a hemoglobinopathy in the newborn. RESULTS: The method described here can distinguish normal ß-globin peptides from the mutant HbS, HbC, HbE, HbD-Los Angeles and HbO-Arab peptides, as well as normal α-globin peptide from the mutant HbG-Philadelphia peptide, allowing the identification of unaffected heterozygotes such as HbAS, and of compound heterozygotes such as HbASG-Philadelphia. CONCLUSIONS: This HPLC-ESI-MS/MS analytical approach provides information that is not available from traditional hemoglobin analyses such as isoelectric focusing and HPLC-UV. It is also capable of determining the amino acid sequence of hemoglobin peptides, potentially allowing the detection of numerous hemoglobinopathies resulting from point mutations.