Jennifer L. Geurts

Genomics in Clinical Practice: Lessons from the Front Lines

This Commentary explores the challenges in launching a medical genomics clinic for whole genome sequencing and analysis of patient samples. The price of whole-genome and -exome sequencing has fallen to the point where these methods can be applied to clinical medicine. Here, we outline the lessons we have learned in converting a sequencing laboratory designed for research into a fully functional clinical program.

Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review.

BACKGROUND Mutations in BRCA1 or BRCA2 genes results in an elevated risk for developing both breast and ovarian cancers over the lifetime of affected carriers. General surgeons may be faced with questions about surgical risk reduction and survival benefit of prophylactic surgery. METHODS A systematic literature review was performed using the electronic databases PubMed, OVID MEDLINE, and Scopus comparing prophylactic surgery vs observation with respect to breast and ovarian cancer risk reduction and mortality in BRCA mutation carriers. RESULTS Bilateral risk-reducing mastectomy provides a 90% to 95% risk reduction in BRCA mutation carriers, although the data do not demonstrate improved mortality. The reduction in ovarian and breast cancer risks using risk-reducing bilateral salpingo-oophorectomy has translated to improvement in survival. CONCLUSIONS Clinical management of patients at increased risk for breast cancer requires consideration of risk, patient preference, and quality of life.

Challenges to clinical utilization of hereditary cancer gene panel testing: perspectives from the front lines

AbstractNext generation sequencing (NGS) technology is rapidly being implemented into clinical practice. Qualitative research was performed to gain an improved understanding of the landscape surrounding the use of NGS in cancer genetics. A focus group was conducted at the Wisconsin Cancer Risk Programs Network biannual meeting. Free flowing discussion with occasional open-ended questions provided insights into the use of NGS. 19 genetic counselors and medical professionals participated. Three major themes were identified with respect to NGS and its use in cancer genetics: knowledge gaps, the evolving clinician role, and uncertain utility. Several corresponding subthemes were identified. With respect to knowledge gaps, participants expressed concern regarding unexpected results and variants of unknown significance, lack of data about NGS findings, absence of standardization regarding use of NGS and guidelines for interpretation, and discomfort with new technology. Regarding the evolving clinician role, necessary changes to the roles of genetic counselors and physicians were noted, as was the resultant impact on care received by patients and their families. Finally, the clinical and economic utility of NGS was questioned. While a shift from traditional Sanger sequencing to NGS is occurring in molecular genetic testing for disease susceptibility, there are several obstacles that need to be overcome before widespread adoption of this technology can occur. Furthermore, key aspects of NGS and it utility remain unexplored. Continued investigation into these subjects is necessary before this technology will consistently be of benefit to patients and their families.

Hereditary Syndromes Involving Pheochromocytoma and Paraganglioma

Pheochromocytomas are neural crest-derived tumors of the adrenal medulla; paragangliomas are extra-adrenal pheochromocytomas. An accurate family and medical history is required to determine the risk for an inherited syndrome. All patients with a pheochromocytoma or paraganglioma should be offered genetic counseling. The qualifications for genetic testing are depending on age at diagnosis, tumor location, biochemistries, malignant behavior, and family history, in order to balance mutation detection rate and cost of testing.

Tubulo-papillary adrenocortical adenoma in a patient with familial adenomatous polyposis: A morphologic, ultrastructural and molecular study

Patients with familial adenomatous polyposis have a higher incidence for developing adrenal neoplasms, most of which are nonfunctioning with conventional histologic appearance. We report a patient with a history of multiple colon polyps who developed an adrenocortical adenoma with unusual morphology. The tumor showed a tubulopapillary architecture and plasmacytoid cytomorphology that were distinct from conventional adrenocortical adenomas. β-Catenin stain showed aberrant nuclear positivity in the tumor, suggesting an altered β-catenin-related pathway. The unusual morphology prompted molecular characterization, and sequencing demonstrated the patient to be germline heterozygous for a 5-base-pair APC deletion at codon 1309 with loss of heterozygosity in the tumor. Our study provides further evidence of genetic predisposition to extraintestinal tumors in the familial adenomatous polyposis population.

Implementation of a quality improvement project for universal genetic testing in women with ovarian cancer

OBJECTIVE The National Comprehensive Cancer Network recommends all women with ovarian cancer be offered genetic testing. Despite a decade of endorsement, many oncology practitioners have yet to make this a part of routine practice. Referral to genetic counseling and completion of genetic testing among patients at substantial risk of germline mutations are significantly lacking, adversely affecting patient care and squandering an opportunity to maximize cancer prevention efforts. This project determined the impact and feasibility of implementing a basic model for universal referral to genetic counseling and completion of genetic testing in women with a diagnosis of ovarian cancer in an academic gynecology oncology practice with access to electronic health records (EHRs). METHODS Patients diagnosed with ovarian cancer from January 2008 to November 2013 were retrospectively reviewed to determine the baseline referral rate for genetic counseling and testing completion in our practice. Implementation of a process change model combining provider training, patient education, enhanced electronic health record documentation and improved patient appointment scheduling strategies were implemented. We then prospectively collected data on all newly diagnosed ovarian cancer patients that had not already undergone genetic testing presenting from December 1, 2013 to November 30, 2016. RESULTS Genetic referral rates, genetic counseling and testing completion rates were markedly improved. Pre-implementation our genetic testing rate was 27% and post implementation our testing rate was 82% (p-value≤0.001). CONCLUSIONS Low cost interventions that target education of both providers and patients regarding the importance of genetic testing along with utilization of the EHR and streamlined patient appointment services can significantly increase rates of genetic testing completion.

Genetic Evaluation of the Patient with Medullary Thyroid Cancer

The hereditary form of medullary thyroid cancer (MTC) is termed multiple endocrine neoplasia type 2 (MEN2). The RET gene is the only gene known to cause MEN2 syndrome, and up to 98 % of patients with MEN2 have an identifiable pathogenic mutation in this gene.