Large, Prospective Analysis of the Reasons Patients Do Not Pursue BRCA Genetic Testing Following Genetic Counseling

Genetic counseling (GC) and genetic testing (GT) identifies high‐risk individuals who benefit from enhanced medical management. Not all individuals undergo GT following GC and understanding the reasons why can impact clinical efficiency, reduce GT costs through appropriate identification of high‐risk individuals, and demonstrate the value of pre‐GT GC. A collaborative project sponsored by the Michigan Department of Health and Human Services prospectively collects anonymous data on BRCA‐related GC visits performed by providers in Michigan, including demographics, patient/family cancer history, GT results, and reasons for declining GT. From 2008 to 2012, 10,726 patients underwent GC; 3476 (32.4%) did not pursue GT. Primary reasons included: not the best test candidate (28.1%), not clinically indicated (23.3%), and insurance/out of pocket cost concerns (13.6%). Patient disinterest was the primary reason for declining in 17.1%. Insurance/out of pocket cost concerns were the primary reason for not testing in 13.4% of untested individuals with private insurance. Among untested individuals with breast and/or ovarian cancer, 22.5% reported insurance/out of pocket cost concerns as the primary reason for not testing and 6.6% failed to meet Medicare criteria. In a five‐year time period, nearly one‐third of patients who underwent BRCA GC did not pursue GT. GT was not indicated in almost half of patients. Insurance/out of pocket cost concerns continue to be barriers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146968/1/jgc40859.pd

Cell‐free DNA results lead to unexpected diagnosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137758/1/ccr31051_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137758/2/ccr31051.pd

Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1 / BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1 /2 mutations, as well as a potential therapeutic target, TSAd

Variants in sample in genes associated with breast or ovarian cancer.

<p>Variants in sample in genes associated with breast or ovarian cancer.</p

OCF28 kindred.

<p>Arrow indicates patient OCF28-1.</p

High impact mutations in DNA repair and cell cycle control genes, not Featured on HBOC testing panels.

<p>High impact mutations in DNA repair and cell cycle control genes, not Featured on HBOC testing panels.</p

Reanalysis of <i>BRCA1/2</i> negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability

<div><p>While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either <i>BRCA1</i> or <i>BRCA2</i>. <i>In silico</i> SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (<i>RAD51D</i>, <i>ATM</i>). In addition, we found a pathogenic <i>FANCM</i> variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in <i>ATM</i> (n = 6) and <i>PALB2</i> (n = 5). The <i>BRCA2</i> variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including <i>CHEK1</i>, <i>TP53I3</i>, <i>REC8</i>, <i>HMMR</i>, <i>RAD52</i>, <i>RAD1</i>, <i>POLK</i>, <i>POLQ</i>, and <i>MCM4</i>. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting <i>BRCA1/2</i> negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.</p></div