Journal of Personalized Medicine

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9 pages, 218 KiB

Open AccessFeature PaperArticle

Challenges to Building a Gene Variant Commons to Assess Hereditary Cancer Risk: Results of a Modified Policy Delphi Panel Deliberation

by Mary A. Majumder, Matthew L. Blank, Janis Geary, Juli M. Bollinger, Christi J. Guerrini, Jill Oliver Robinson, Isabel Canfield, Robert Cook-Deegan and Amy L. McGuire

J. Pers. Med. 2021, 11(7), 646; https://doi.org/10.3390/jpm11070646 - 8 Jul 2021

Cited by 5 | Viewed by 2778

Abstract

Understanding the clinical significance of variants associated with hereditary cancer risk requires access to a pooled data resource or network of resources—a “cancer gene variant commons”—incorporating representative, well-characterized genetic data, metadata, and, for some purposes, pathways to case-level data. Several initiatives have invested [...] Read more.

Understanding the clinical significance of variants associated with hereditary cancer risk requires access to a pooled data resource or network of resources—a “cancer gene variant commons”—incorporating representative, well-characterized genetic data, metadata, and, for some purposes, pathways to case-level data. Several initiatives have invested significant resources into collecting and sharing cancer gene variant data, but further progress hinges on identifying and addressing unresolved policy issues. This commentary provides insights from a modified policy Delphi process involving experts from a range of stakeholder groups involved in the data-sharing ecosystem. In particular, we describe policy issues and options generated by Delphi participants in five domains critical to the development of an effective cancer gene variant commons: incentives, financial sustainability, privacy and security, equity, and data quality. Our intention is to stimulate wider discussion and lay a foundation for further work evaluating policy options more in-depth and mapping them to those who have the power to bring about change. Addressing issues in these five domains will contribute to a cancer gene variant commons that supports better care for at-risk and affected patients, empowers patient communities, and advances research on hereditary cancers. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

14 pages, 1482 KiB

Open AccessArticle

Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies

by Ky’Era V. Actkins, Heather K. Beasley, Annika B. Faucon, Lea K. Davis and Amos M. Sakwe

J. Pers. Med. 2021, 11(7), 642; https://doi.org/10.3390/jpm11070642 - 6 Jul 2021

Cited by 2 | Viewed by 2470

Abstract

Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms [...] Read more.

Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms. Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies. Our data suggest that expression of CaSR variants at rs1801725 is associated with a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part to cancer-induced hypercalcemia and/or tumor immune suppression. Screening of patients for CASR variants at this locus may lead to improved management of high calcium associated tumor progression. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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15 pages, 732 KiB

Open AccessArticle

Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families

by Maria Fonfria, Inmaculada de Juan Jiménez, Isabel Tena, Isabel Chirivella, Paula Richart-Aznar, Angel Segura, Ana Beatriz Sánchez-Heras and Eduardo Martinez-Dueñas

J. Pers. Med. 2021, 11(6), 548; https://doi.org/10.3390/jpm11060548 - 12 Jun 2021

Cited by 4 | Viewed by 2144

Abstract

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with [...] Read more.

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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12 pages, 1019 KiB

Open AccessArticle

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening

by Nora B. Henrikson, Paula Blasi, Marlaine Figueroa Gray, Brooks T. Tiffany, Aaron Scrol, James D. Ralston, Stephanie M. Fullerton, Catherine Y. Lim, John Ewing and Kathleen A. Leppig

J. Pers. Med. 2021, 11(6), 538; https://doi.org/10.3390/jpm11060538 - 10 Jun 2021

Cited by 16 | Viewed by 2536

Abstract

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade [...] Read more.

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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14 pages, 19281 KiB

Open AccessArticle

Clinical Utility of microRNAs in Exhaled Breath Condensate as Biomarkers for Lung Cancer

by Carlos Pérez-Sánchez, Nuria Barbarroja, Lucas C. Pantaleão, Laura M. López-Sánchez, Susan E. Ozanne, Bernabé Jurado-Gámez, Enrique Aranda, Chary Lopez-Pedrera and Antonio Rodríguez-Ariza

J. Pers. Med. 2021, 11(2), 111; https://doi.org/10.3390/jpm11020111 - 9 Feb 2021

Cited by 14 | Viewed by 4081

Abstract

This study represents a novel proof of concept of the clinical utility of miRNAs from exhaled breath condensate (EBC) as biomarkers of lung cancer (LC). Genome-wide miRNA profiling and machine learning analysis were performed on EBC from 21 healthy volunteers and 21 LC [...] Read more.

This study represents a novel proof of concept of the clinical utility of miRNAs from exhaled breath condensate (EBC) as biomarkers of lung cancer (LC). Genome-wide miRNA profiling and machine learning analysis were performed on EBC from 21 healthy volunteers and 21 LC patients. The levels of 12 miRNAs were significantly altered in EBC from LC patients where a specific signature of miR-4507, miR-6777-5p and miR-451a distinguished these patients with high accuracy. Besides, a distinctive miRNA profile between LC adenocarcinoma and squamous cell carcinoma was observed, where a combined panel of miR-4529-3p, miR-8075 and miR-7704 enabling discrimination between them. EBC levels of miR-6777-5p, 6780a-5p and miR-877-5p predicted clinical outcome at 500 days. Two additional miRNA signatures were also associated with other clinical features such as stage and invasion status. Dysregulated EBC miRNAs showed potential target genes related to LC pathogenesis, including CDKN2B, PTEN, TP53, BCL2, KRAS and EGFR. We conclude that EBC miRNAs might allow the identification, stratification and monitorization of LC, which could lead to the development of precision medicine in this and other respiratory diseases. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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22 pages, 3761 KiB

Open AccessArticle

Expression of ATP/GTP Binding Protein 1 Has Prognostic Value for the Clinical Outcomes in Non-Small Cell Lung Carcinoma

by Hee Jeong Kwak, Minchan Gil, Hee Sung Chae, Jaekwon Seok, Nagasundarapandian Soundrarajan, Subbroto Kumar Saha, Aram Kim, Kyoung Sik Park, Chankyu Park and Ssang-Goo Cho

J. Pers. Med. 2020, 10(4), 263; https://doi.org/10.3390/jpm10040263 - 2 Dec 2020

Cited by 1 | Viewed by 2437

Abstract

ATP/GTP binding protein 1 (AGTPBP1) encodes a crucial protein, cytosolic carboxypeptidase 1 (CCP1), which plays a role in modulating the polyglutamylation of tubulin and has been studied in degenerative diseases. However, the role of AGTPBP1 in malignancy has not been completely [...] Read more.

ATP/GTP binding protein 1 (AGTPBP1) encodes a crucial protein, cytosolic carboxypeptidase 1 (CCP1), which plays a role in modulating the polyglutamylation of tubulin and has been studied in degenerative diseases. However, the role of AGTPBP1 in malignancy has not been completely studied yet. In this study, we examined the role of AGTPBP1 in cancer progression, its association with patient survival, and related mechanisms in lung cancer, using the A549 cell line and lung cancer gene expression datasets. AGTPBP1 knockdown increased the proliferation, migration, sphere formation, and drug resistance of A549 cells. Lung cancer datasets revealed significantly lower mRNA and protein expression levels of AGTPBP1 in lung cancer tissues, as compared to those in normal tissues. Importantly, AGTPBP1 expression positively correlated with patient survival. Analysis of co-expressed genes revealed that AGTPBP1 expression positively correlated with immune infiltration in lung cancer. Our results conclusively suggested that AGTPBP1 expression was correlated with cancer progression and immune infiltration in lung cancer. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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12 pages, 3834 KiB

Open AccessCase Report

Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas

by Karen M. Huelsman, Jack B. Basil, Rebecca Sisson, Lindsay R. Lipe, Brett Mahon and David J. Draper

J. Pers. Med. 2021, 11(7), 634; https://doi.org/10.3390/jpm11070634 - 5 Jul 2021

Cited by 1 | Viewed by 3862

Abstract

Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient [...] Read more.

Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient with germline PMS2 Lynch syndrome and clinical tumor analysis leading to insight regarding the origin and cause of these tumors, with potential therapy options. PMS2-related SEOC is less common due to lower risks for these cancers associated with germline PMS2 mutation compared to other Lynch genes. While synchronous cancers are not common, they are more likely to occur with Lynch syndrome. Tumor profiling with next-generation sequencing of 648 genes identified sixteen shared somatic actionable and biologically relevant mutations. This case is a rare example of a patient with PMS2 germline Lynch syndrome with shared somatic variants that demonstrate clonality of the two tumors arising from one common site. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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12 pages, 3787 KiB

Open AccessStudy Protocol

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program

by Anna DiNucci, Nora B. Henrikson, M. Cabell Jonas, Sundeep Basra, Paula Blasi, Jennifer Brown, Edward D. Esplin, Dina Hassen, Jing Hao, Yirui Hu, Tracey Klinger, Ilene Ladd, Kathleen Leppig, Meredith Lewis, Michelle Meyer, Steven Ney, Arvind Ramaprasan, Katrina Romagnoli, Zachary Salvati, Aaron Scrol, Rachel Schwiter, Leigh Sheridan, Brinda Somasundaram, Pim Suwannarat, Jennifer K. Wagner and Alanna K. Rahm Show full author list Hide full author list

J. Pers. Med. 2021, 11(6), 543; https://doi.org/10.3390/jpm11060543 - 11 Jun 2021

Cited by 3 | Viewed by 4471

Abstract

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. “Traceback” cascade testing —outreach to potential probands and relatives—is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking [...] Read more.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. “Traceback” cascade testing —outreach to potential probands and relatives—is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program’s feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program’s feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs. Full article

(This article belongs to the Special Issue Cancer Genetics and Genomics Research)

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