Yelena Kemel

Sources of uncertainty about daughters' breast cancer risk that emerge during genetic counseling consultations.

Uncertainty is central to the experience of genetic decision making and counseling about cancer risk. Women seeking genetic counseling about their breast cancer risk may experience a great deal of uncertainty about issues related to their daughters. We used a theory of Communication and Uncertainty Management to guide analysis of sources of uncertainty about daughters that emerged during 16 video-recorded and transcribed conversations between mothers at risk for a BRCA 1/2 mutation and their genetic healthcare practitioners. An interpretive design and constant comparative method revealed three dominant patterns or themes representing sources of uncertainty mothers have relating to their daughters: disease risk, future cancer screening, and communication of related information to daughters. Both practitioners and mothers discussed these aspects of uncertainty. The findings identify the significant role uncertainty and familial concerns play in mothers’ genetic testing decision making process. To assist genetic practitioners, we highlight daughter-related concerns that mothers are uncertain about and which are vital to their genetic counseling needs.

Incorporating Information Regarding Preimplantation Genetic Diagnosis Into Discussions Concerning Testing and Risk Management for BRCA1/2 Mutations A Qualitative Study of Patient Preferences

Studies have shown that BRCA1/2 mutation carriers are interested in learning about reproductive options such as preimplantation genetic diagnosis (PGD) to prevent passing their risk onto their children. However, attitudes vary widely, and the procedure raises complex ethical and psychosocial issues. This complexity, plus the highly technical nature of PGD, makes it difficult to integrate PGD information into genetic counseling sessions that already cover probabilistic, emotionally charged risk information.

Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes

Micro‐Abstract Renal medullary carcinoma (RMC) is a rare kidney cancer with poor outcomes. We analyzed treatment outcomes in patients with RMC and performed targeted sequencing of tumors to identify unique molecular features. Although responses to platinum‐based therapy were found, these were short‐lived. There was uniform loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through translocations and deletions, and further research should go into targeting this pathway. Background: Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods: This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next‐generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan–Meier method. Results: The median age in the cohort was 28 (range, 12‐72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1‐10.9) and for 12 patients who received platinum‐based therapy, median progression‐free survival was 2.5 months (95% CI, 1.2‐not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next‐generation targeted sequencing showed no recurring mutations. Conclusions: Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Billing and Record-Keeping for Familial Cancer Risk Counseling: A National Survey

We surveyed 111 genetic counselors providing cancer risk counseling (CRC) in order to document their billing and record-keeping practices. Of the 75 respondents, billing was generally done under the supervising physician with a wide variation in charges. Follow-up telephone interviews with 28 counselors who charge patients revealed that billing was usually done using the CPT codes for consultations, and the ICD-9 diagnostic codes for cancer (if applicable), a medical complaint, or a family history of cancer code. Most counselors exclude some clinical information from the patients medical record. In consultation notes, 81% of counselors document a discussion of genetic testing, but only 37% document the patients actual testing decision, and only 19% document test results. In anticipation of increased referrals for CRC, data are needed on the components of a CRC visit, the amount of time required to provide CRC, patient outcomes measures, and charges and reimbursement. The feasibility and advisability of keeping results separate from the patients medical record also needs to be addressed.

Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes

In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes. The GSVS then reviewed and analyzed available resources of relevant somatic data, and performed integrative germline variant curation exercises. The committee determined that somatic hotspots could be systematically integrated into moderate evidence of pathogenicity (PM1). Tumor RNA sequencing data showing altered splicing may be considered as strong evidence in support of germline pathogenicity (PVS1) and tumor phenotypic features such as mutational signatures be considered supporting evidence of pathogenicity (PP4). However, at present, somatic data such as focal loss of heterozygosity and mutations occurring on the alternative allele are not recommended to be systematically integrated, instead, incorporation of this type of data should take place under the advisement of multidisciplinary cancer center tumor‐normal sequencing boards.

Towards automation of germline variant curation in clinical cancer genetics

Cancer care professionals are confronted with interpreting results from multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches, requiring aggregation of multiple lines of evidence from diverse resources. The burden of evidence for each variant to meet thresholds for pathogenicity or actionability now poses a growing challenge for those seeking to counsel patients and families following germline genetic testing. A computational algorithm that automates, provides uniformity and significantly accelerates this interpretive process is needed. The tool described here, Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources. We compared expert manually curated variant data from studies on (i) prostate cancer (ii) breast cancer and (iii) ClinVar to assess performance. PathoMAN achieves high concordance (83.1% pathogenic, 75.5% benign) and negligible discordance (0.04% pathogenic, 0.9% benign) when contrasted against expert curation. Some loss of resolution (8.6% pathogenic, 23.64% benign) and gain of resolution (6.6% pathogenic, 1.6% benign) was also observed. We highlight the advantages and weaknesses related to the programmable automation of variant classification. We also propose a new nosology for the five ACMG classes to facilitate more accurate reporting to ClinVar. The proposed refinements will enhance utility of ClinVar to allow further automation in cancer genetics. PathoMAN will reduce the manual workload of domain level experts. It provides a substantial advance in rapid classification of genetic variants by generating robust models using a knowledge-base of diverse genetic data https://pathoman.mskcc.org.

Germline SDHA mutations in children and adults with cancer

Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma (n = 1), breast (n = 1), colon (n = 1), renal (n = 1), melanoma and uterine (n = 1), prostate (n = 1), endometrial (n = 1), bladder (n = 1), and gastrointestinal stromal tumor (GIST) (n = 2). Immunohistochemical staining and assessment of patient tumors for second hits and loss of heterozygosity in SDHA confirmed GIST as an SDHA-associated tumor and suggests SDHA germline mutations may be a driver in neuroblastoma tumorigenesis.

Abstract 4280:FH(rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer

Fumarate Hydratase (FH) mutations underpin the autosomal recessive syndrome Fumarate Hydratase deficiency and the autosomal dominant syndrome Hereditary Leiomyomatous and Renal Cell Carcinoma (HLRCC). The variant rs367543046, a duplication leading to p. Lys477_Asn478insLys in FH has strong evidence for risk towards fumarate hydratase deficiency when occurring in trans to another germline alteration in the FH gene. In addition, this variant in the heterozygous state has been reported in ClinVar to predispose to the autosomal dominant condition HLRCC, given other heterozygous mutations have shown to be pathogenic. Population level data is sparse to determine the variant’s impact in the heterozygous state. Here, we show in a series of 1375 cancer cases the (rs367543046, chr1: 241661227 A/ATTT), variant detected in 7 (0.5%) individuals with cancer. One patient with bladder cancer had a history of uterine leiomyomas, but the immunohistochemistry for 2SC was negative, suggesting that the leiomyomas were not associated with HLRCC. None of the other 6 carriers of this variant had any features of HLRCC. Notably, this variant was not detected in any of the patients with renal cancer (n=178) participating in the study. Since 4/7 prostrate cancer patients of Ashkenazi ethnicity harbored this variant, we performed a genetic epidemiology study using 856 Ashkenazi Jewish prostate cancer patients. The allele frequencies were compared with 557 Ashkenazi Jewish non-cancer controls. A fisher’s two sided exact test showed that the variant is not associated with prostate cancer in Jews (P=1, OR 1.12(CI 95% 0.21-7.25). Our findings suggest that the variant, which is pathogenic for autosomal recessive fumarate hydratase deficiency does not confer pathogenicity in the heterozygous form for Hereditary Leiomyomatous and Renal Cell Carcinoma or prostate cancer. Citation Format: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang. FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2017-4280