Elaine Hiller

BRCAPRO Validation, Sensitivity of Genetic Testing of BRCA1/BRCA2, and Prevalence of Other Breast Cancer Susceptibility Genes

PURPOSE To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.

Population-Wide Screening for Germline BRCA1 and BRCA2 Mutations: Too Much of a Good Thing?

Germline testing for highly penetrant mutations in cancer susceptibility genes such as BRCA1 and BRCA2 (BRCA1/2) can prevent cancer and save lives. Inherited BRCA1/2 mutations confer a 39% to 85% lifetime risk of female breast cancer and an 11% to 62% lifetime risk of ovarian cancer. Identifying BRCA1/2 mutation carriers thus allows for prophylactic surgeries, which can markedly decrease cancer incidence, morbidity, and mortality. Despite these benefits and increasing public awareness, a low fraction (35% in a recent Israeli study) of women with high-risk histories have undergone BRCA1/2 testing. Moreover, women from families with few female relatives are unlikely to recognize their risk of carrying a BRCA1/2 mutation until they themselves develop cancer. Recently, citing the impact of riskreducing surgeries, King et al published a high-profile appeal for BRCA1/2 mutation screening to be offered to all US women at age 30 years. King is to be commended for stimulating a serious discussion on the potential impact of bringing modern genetic medicine to the general population in a compelling circumstance. However, because testing all women for BRCA1/2 mutations would represent the first population-based screening for a hereditary cancer syndrome, careful consideration of the potential limitations, risks, and benefits of population-wide BRCA1/2 testing is essential. Currently, genetic screening efforts in the general population examine newborns for rare recessive disorders (eg, phenylketonuria, beta thalassemia) or screen prenatally for carriers of populationdependent recessive conditions (eg, Tay-Sachs, cystic fibrosis), seeking to prevent morbidity and mortality from childhood-onset diseases. In the case of autosomal dominantly inherited BRCA1/2 mutations, the goal is to reduce suffering and mortality from associated adult-onset malignancies, particularly in individuals who would not otherwise be aware of their cancer risk. Demonstration studies in the Ashkenazi Jewish population have shown that screening for its three BRCA1/2 founder mutations (with a combined 1-in-40 prevalence among unselected Ashkenazi Jews) is cost-effective and identifies carriers who would not have been suspected on the basis of their family cancer history. Citing a recent study of population-wide screening for the Ashkenazi founder mutations in Israel, King et al claim that the high penetrance of BRCA1/2 mutations is independent of whether patients who carry the mutations are ascertained on the basis of family history. However, all such studies examined Ashkenazi founder mutations only, which constitute more than 90% of mutations in the Ashkenazi population, thereby limiting generalizability to other populations. In the general US population, in which combined prevalence of a diverse array of BRCA1/2 mutations is 10-fold lower, widespread screening would have different performance characteristics than in the Ashkenazim. Whether the assortment of BRCA1/2 mutations found in non-Ashkenazi populations would have the same penetrance in population-based ascertainment as they do in clinicbased patients is unknown.

The Experience of Leader-Led Peer Supervision: Genetic Counselors' Perspectives.

As we proceed through our professional lives, it is essential that we challengeourselves in order to continue to develop our genetic counseling skills. Conferences, workshops,post-graduate courses, journal clubs, and involvement in professional organizations havebecome the traditional methods of continuing education for post-graduate geneticcounselors. While these forums address the need to stay updated on scientific orinformation-based topics, there is little available to counselors to promote growth incounseling skills. A group of Boston-based genetic counselors describe how their leader-ledsupervision group has established a setting to meet the needs of its members both forsupport and continued counseling training. We outline here the evolution of this group andhow it has become a valued part of our professional lives. We feel that the model of leader-ledpeer supervision holds great value in helping genetic counselors continue to enhancetheir interpersonal skills in a supportive, safe, and challenging environment. It is our hopethat others will elect to form similar groups in their own communities, thereby creating newopportunities for growth within the genetic counseling profession.

Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study

Purpose:Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care.Methods:One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences.Results:At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach.Conclusion:The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017

Exome sequencing reveals recurrent germ line variants in patients with familial Waldenström macroglobulinemia.

Familial aggregation of Waldenström macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first-degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germ line DNA obtained from 4 family members in which coinheritance for WM was documented in 3 of them, and screened additional independent 246 cases by using gene-specific mutation sequencing. Among the shared germ line variants, LAPTM5(c403t) and HCLS1(g496a) were the most recurrent, being present in 3/3 affected members of the index family, detected in 8% of the unrelated familial cases, and present in 0.5% of the nonfamilial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5(c403t) and HCLS1(g496a) may represent predisposition alleles in patients with familial WM.

Cancer Genetic Counseling

Our fundamental understanding of carcinogenesis has expanded dramatically over the past five years. Of foremost importance has been the discovery of genes that, when mutated in the germline, confer high risks of specific malignancies. The translation of these laboratory findings into clinical practice has led to the creation of a new medical subspecialty termed cancer genetic counseling. Cancer genetic counseling is defined as a communication process concerning an individual’s risk of developing specific inherited forms of cancer. This risk may be higher than or similar to the general population risks of cancer. Cancer genetic counseling can, but does not always, lead to genetic testing. The genetic counseling process involves: 1) obtaining detailed family, medical, and lifestyle histories; 2) documentation of cancer-related diagnoses; 3) pedigree analysis; 4) risk assessment and counseling; 5) general discussion of options for early detection and prevention; and 6) provision of genetic testing when appropriate. This chapter provides an overview of cancer genetic counseling, including a general description of the providers and patients involved, the cancer genetic-counseling process in a high-risk clinical setting and a predisposition-testing program, the provision of genetic counseling for selected hereditary-cancer syndromes, and case examples to highlight some of the complexities inherent to this process.

A comparison of cancer risk assessment and testing outcomes in patients from underserved vs. tertiary care settings

In cancer genetics, technological advances (next generation sequencing) and the expansion of genetic test options have resulted in lowered costs and increased access to genetic testing. Despite this, the majority of patients utilizing cancer genetics services lack diversity of gender, ethnicity, and socioeconomic status. Through retrospective chart review, we compared outcomes of cancer genetics consultations at a tertiary cancer center and a Federally Qualified Health Center (FQHC) (58 tertiary and 23 FQHC patients) from 2013 to 2015. The two groups differed in race, ethnicity, use of translator services, and type of insurance coverage. There were also significant differences in completeness of family history information, with more missing information about relatives in the FQHC group. In spite of these differences, genetic testing rates among those offered testing were comparable across the two groups with 74% of tertiary patients and 60% of FQHC patients completing testing. Implementation of community-based cancer genetics outreach clinics represents an opportunity to improve access to genetic counseling services, but more research is needed to develop effective counseling models for diverse patient populations.

Abstract 2570: An integrated germline analysis platform for comprehensive clinical cancer genomics.

Background: In order to apply massively parallel sequencing for use in clinical oncology, we have created algorithms to identify clinically actionable somatic alterations within an individual patient9s tumor exome. To fully implement comprehensive clinical sequencing for cancer patients, a parallel platform for analyzing germline genetic variants is necessary to identify 1) clinically relevant cancer risk, non-cancer disease risk, and pharmacogenomics variants, and 2) germline variants related to clinically relevant somatic alterations. Methods: Databases consisting of genes known to undergo germline alterations that may inform disease risk or pharmacogenomic variation were created by review of publically available resources (e.g. Cancer Gene Census) and augmented with literature review and expert opinion. Whole exome sequencing of normal DNA from prospectively acquired individual patient germline samples was performed using established Broad Institute pipelines for hybrid capture and variant calling. Population frequencies of all non-synonymous variants represented in our clinical germline databases were assessed with Exome Variant Server data, and all variants were cross-referenced with published lists of possibly pathogenic germline variants (e.g. HGMD). Variants with a population frequency of less than 1% that were also present in our clinical germline databases were assigned for high priority review. Integration of germline alterations with somatic data was implemented by computationally searching for germline non-synonymous variants in somatically altered clinically actionable cancer genes or pathways of such genes. All findings were incorporated into a novel web-based decision support system to maximize interpretation access for clinical genetic specialists who determined final classification of the variants. Results: Application of the germline analysis platform to whole exome sequencing data from twelve prospectively acquired clinical patient samples identified a median of 7 [range: 4-10] high priority germline variants warranting subsequent review from among thousands of variants per patient. Integrative analysis of one patient with EGFR mutant lung adenocarcinoma revealed a non-synonymous germline variant in EGFR at another site warranting further exploration. Conclusions: Our germline analysis platform facilitates prospective clinical interpretation of germline genomic variants by prioritizing and representing alterations of potential clinical significance. The platform also integrates germline variants with clinically actionable somatic alterations for enhanced understanding of potential disease drivers at the individual patient level. Implementation of clinical cancer sequencing with germline analyses may directly impact patient care and deepen our understanding of the role of germline variants in cancer epidemiology. Citation Format: Eliezer M. Van Allen, Nikhil Wagle, Adam Keizun, Gregory Kryukov, Aaron McKenna, Franklin Huang, Elaine Hiller, Irene Rainville, Daniel Auclair, Lauren Ambrogio, Stacy Gray, Steven Joffe, Gad Getz, Judy Garber, Levi Garraway. An integrated germline analysis platform for comprehensive clinical cancer genomics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2570. doi:10.1158/1538-7445.AM2013-2570