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PURPOSE Whether individuals with monoallelic FH pathogenic variants (PVs) associated with autosomal recessive fumarate hydratase (FH) deficiency are also at risk of autosomal dominant FH-associated tumors is of paramount clinical importance. METHODS A retrospective study of individuals with a PV in the FH gene identified via multigene panel testing from 2012 to 2019 through a single testing laboratory was performed. Cancer histories of individuals with PVs in FH ( FH PV) were compared to those with PVs associated only with autosomal recessive FH deficiency (FH-d PV) and to FH-negative controls. Cancer histories of individuals with truncating versus nontruncating FH PV were also compared. RESULTS Individuals with FH PV were more likely to have kidney cancer than those with FH-d PV (odds ratio, 9.0; 95% CI, 4.4 to 20.0; P < .001) or FH-negative controls (odds ratio, 7.6; 95% CI, 5.2 to 11.2; P value < .001). The FH PV cohort had kidney cancer at a significantly younger age (median age: 35.0 years; interquartile range, 26.0-45.0 years) than the FH-d PV cohort (median age: 44.5 years; interquartile range, 43.5-53.5 years; P = .011). Within the FH PV cohort, there were no differences in the frequency or age at kidney cancer between those with truncating versus nontruncating PV. CONCLUSION Unlike FH PV, FH-d PV are not associated with kidney cancers at early ages of onset. The FH-d PV cohort had a cancer phenotype that resembled FH-negative controls. These data may inform genetic counseling and risk assessment of individuals with FH-d PV.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

Purpose To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC). Methods We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case–control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals. Results Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1–32.7, p

Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype–phenotype associations among TP53+ panel-ascertained subjects. Between 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results. Subject cancer histories were obtained from test requisition forms. P/LP variants were categorized by type and were examined in relation to phenotype. Loss-of-function (LOF) variants were associated with the earliest age at first cancer, with a median age of 30.5 years (P = 0.014); increased frequency of a sarcoma diagnosis (P = 0.016); and more often meeting classic LFS testing and Chompret 2015 criteria (P = 0.004 and 0.002 respectively), as compared with dominant-negative missense, other missense, or miscellaneous (splice or in-frame deletion) P/LP variant categories. Loss-of-function variants were more often associated with characteristic LFS cancer histories than other variant categories in TP53+ carriers ascertained through multigene panel testing. These findings require validation in other TP53+ cohorts. Genetic counseling for panel-ascertainedTP53+ individuals should reflect the dynamic expansion of the Li–Fraumeni syndrome phenotype.

Background Although rare cancers account for 27% of cancer diagnoses in the US, there is insufficient research on survivorship issues in these patients. An important issue cancer survivors face is an elevated risk of being diagnosed with new primary cancers. The primary aim of this analysis was to assess whether a history of rare cancer increases the risk of subsequent cancer compared to survivors of common cancers. Methods This was a prospective cohort study of 16,630 adults with personal and/or family history of cancer who were recruited from cancer clinics at 14 geographically dispersed US academic centers of the NIH-sponsored Cancer Genetics Network (CGN). Participants’ self-reported cancer histories were collected at registration to the CGN and updated annually during follow-up. At enrollment, 14% of participants reported a prior rare cancer. Elevated risk was assessed via the cause-specific hazard ratio on the time to a subsequent cancer diagnosis. Results After a median follow-up of 7.9 years, relative to the participants who were unaffected at enrollment, those with a prior rare cancer had a 23% higher risk of subsequent cancer (95% CI: -1 to 52%), while those with a prior common cancer had no excess risk. Patients having two or more prior cancers were at a 53% elevated risk over those with fewer than two (95% CI: 21 to 94%) and if the multiple prior cancers were rare cancers, risk was further elevated by 47% (95% CI: 1 to 114%). Conclusion There is evidence suggesting that survivors of rare cancers, especially those with multiple cancer diagnoses, are at an increased risk of a subsequent cancer. There is a need to study this population more closely to better understand cancer pathogenesis. Electronic supplementary material The online version of this article (10.1186/s12885-019-5358-1) contains supplementary material, which is available to authorized users.

Summary: Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of telomere biology disorder who underwent allogeneic transplantation. Patients with TERT rare variants had shorter telomere length (pTERT rare variant. In multivariable analyses, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. According to ACMG/AMP guidelines and Sherloc criteria, 39 TERT rare variants were classified as VUS and one as likely pathogenic. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 36 of 40 variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized and routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion could identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Patient: Female, 62-year-old Final Diagnosis: Medullary thyroid microcarcinoma Symptoms: No pain or swelling in her neck • no dysphagia or odynophagia • no changes in voice Medication: — Clinical Procedure: Genetic analysis Specialty: Genetics Objective: Unusual clinical course Background: RET p.V804M is a known activating oncogenic variant that confers an increased risk for medullary thyroid carcinoma (MTC). Based on age-specific penetrance, the American Thyroid Association (ATA) categorizes this variant as posing moderate risk. Therefore, ATA guidelines endorse prophylactic thyroidectomy for carriers in childhood (by age 5–10 years) or adulthood, or when the serum calcitonin level becomes elevated. The recommendation for thyroidectomy is increasingly controversial due to the recently reported low penetrance of the RET p.V804M variant in a large unbiased ascertainment cohort. Case Report: We describe the unexpected identification of this variant in a 62-year-old woman undergoing broad, multigene cancer panel testing for her personal and family history of breast cancer. There was no known family history of MTC. Biochemical screening prompted by the RET p.V804M result revealed a mildly elevated serum calcitonin. Pathology examination of her thyroidectomy specimen revealed multifocal medullary thyroid microcarcinoma; her sibling’s prophylactic thyroidectomy after a RET p.V840M-positive result similarly revealed early-stage MTC. Conclusions: This report demonstrates the value of genetic counseling, shared decision-making, cascade testing, and timely thyroidectomy in the management of a patient with an unexpected RET p.V804M result.

Objective Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing. Methods Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention. Results Between 2013 and 2015, 88–92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p Conclusions Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.

Prior studies of the germline landscape of renal cell carcinoma (RCC) have centered around predominantly white patients of European ancestry. We examined the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants were found in 17%, among which 10.3% harbored ≥1 clinically actionable germline variant with potential preventive or therapeutic utility. Patients with African ancestry harbored significantly more P/LP variants in FH compared to patients of European ancestry. Patients with European ancestry had significantly more P/LP variants in CHEK2 and overall had more actionable variants compared to patients with African ancestry. This work helps better understand the underlying biological differences in RCC between Africans and Europeans. In addition, this work may pave the way to a much more comprehensive and global genomic characterization of underrepresented populations.

Background Li-Fraumeni syndrome (LFS) has traditionally been identified by single-gene testing (SGT) of TP53 triggered by clinical criteria, but the widespread use of multigene panel tests (MGPTs) has upended this paradigm. We sought to compare the personal and family cancer histories of TP53-positive result (TP53+) carriers who were identified by either MGPT or SGT. Methods Of 44 310 individuals who underwent testing of TP53 in a single clinical diagnostic laboratory between 2010 and 2014, 44 086 (40 885 MGPT and 3201 SGT) met study eligibility criteria. Personal cancer histories were available for 38 938 subjects. The frequency of germline TP53 results and various phenotypic manifestations were compared according to test type. All statistical tests were two-sided. Results MGPT TP53+ individuals (n = 126) had an older median age at first cancer than SGT TP53+ carriers (n = 96; women: median = 36 vs 28 years, P < .001; and men: median = 40 vs 15 years, P = .004). The median age of breast cancer diagnosis was 40 years in MGPT TP53+ women vs 33 years in SGT TP53+ women (P < .001). In both cohorts, childhood and LFS core cancers, and for women, multiple primary cancers (not multiple breast tumors), were associated with TP53+ results. Established LFS testing criteria were less often met by MGPT TP53+ individuals. Conclusions MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks.

Von Hippel-Lindau (VHL) syndrome is a hereditary cancer genetic condition associated with inactivating pathogenic alterations in the VHL tumor suppressor gene located at 3p (short arm of chromosome 3). Classic features of VHL include clear cell renal cell carcinoma, hemangioblastomas of the brain, spinal cord, and retina, pheochromocytoma, pancreatic cysts, and neuroendocrine tumors. Two sets of genomic information may be available from patients with VHL: the germline data showing the constitutional genetic profile and somatic profile obtained from patient tumor(s). Here we present both somatic and germline dataset from heterozygous carriers of germline VHL variants who exhibit non-syndromic VHL phenotypes. This data description article accompanies the paper “Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: an integrated evaluation of germline and somatic genomic results by Huma Q. Rana, Diane R. Koeller, Alison Schwartz, Danielle K. Manning, Katherine A. Schneider, Katherine M. Krajewski, Toni K. Choueiri, Neal I. Lindeman, Judy E. Garber, Arezou A. Ghazani. We provide next generation sequencing (NGS) data obtained from DNA from tumors (renal cancer, bladder cancer, and cerebral hemangioblastoma) of three VHL carriers. The somatic dataset was analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs) in 447 cancer genes, and structural variation (SVs) in 191 regions across 60 genes for rearrangements. We also present germline raw NGS data and analyzed SNV and CNV data in exonic regions of 133 hereditary cancer genes obtained from the peripheral blood of two VHL carriers.

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. 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. 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. 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

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers’ behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors.

Paraganglioma, HIF-2α, and Cyanotic Heart Disease Four of five patients with paragangliomas and pheochromocytomas who had received a diagnosis of congenital cyanotic heart disease had mutant HIF-2α. This contrasts with the prevalence of mutant HIF-2 in these tumor types in the absence of cyanotic heart disease (6 to 10%).

Importance Performing DNA genetic testing (DGT) for hereditary cancer genes is now a well-accepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians’ ability to accurately apply strategies for cancer risk reduction and treatment. Objective To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition. Design, Setting, and Participants Diagnostic study in which patients and/or families with inconclusive variants detected by DGT in genes associated with hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer sent blood samples for RGT from March 2016 to April 2018. Clinicians who ordered genetic testing and received a reclassification report for these variants were surveyed to assess whether RGT-related variant reclassifications changed clinical management of these patients. To quantify the potential number of tested individuals who could benefit from RGT, a cohort of 307 812 patients who underwent DGT for hereditary cancer were separately queried to identify variants predicted to affect splicing. Data analysis was conducted from March 2016 and September 2018. Main Outcomes and Measures Variant reclassification outcomes following RGT, clinical management changes associated with RGT-related variant reclassifications, and the proportion of patients who would likely be affected by a concurrent DGT and RGT multigene panel testing approach. Results In total, 93 if 909 eligible families (10.2%) submitted samples for RGT. Evidence from RGT clarified the interpretation of 49 of 56 inconclusive cases (88%) studied; 26 (47%) were reclassified as clinically actionable and 23 (41%) were clarified as benign. Variant reclassifications based on RGT results changed clinical management recommendations for 8 of 18 patients (44%) and 14 of 18 families (78%), based on responses from 18 of 45 clinicians (40%) surveyed. A total of 7265 of 307 812 patients who underwent DGT had likely pathogenic variants or variants of uncertain significance potentially affecting splicing, indicating that approximately 1 in 43 individuals could benefit from RGT. Conclusions and Relevance In this diagnostic study, conducting RNA testing resolved a substantial proportion of variants of uncertain significance in a cohort of individuals previously tested for cancer predisposition by DGT. Performing RGT might change the diagnostic outcome of at least 1 in 43 patients if performed in all individuals undergoing genetic evaluation for hereditary cancer.

Background Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. Methods Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. Results Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. Conclusions The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

10595 Background: Multiple primary cancers (MPCs) are a hallmark of cancer predisposition syndromes. We aim to characterize the frequency of germline pathogenic/likely pathogenic variants (PVs) among patients with MPCs. Herein we report the frequency of PVs by sex, number of cancers and age at diagnosis among a laboratory-based cohort of patients with MPCs. Methods: Patients with MPCs who underwent germline genetic testing with Ambry Genetics from 3/2012 to 12/2016 were included in our cohort. Eligible individuals had multigene panel testing, which included 21 genes, at minimum: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Clinical factors including age at diagnosis, age at testing and cancer type were obtained from test requisition forms and clinical notes. Patients with > 1 PVs were excluded from the analysis. Using Rv.3.3.3., the frequencies of PVs by sex, number of cancers and age at diagnosis were compared using two-sided χ2 tests or Fisher’s exact test when the number was < 10. Results: Of the 9820 patients with MPCs tested for the 21 genes above, 104 (1.1%) had multiple PVs and were excluded. Among the remaining 9716 patients in the analytic cohort, most were female (91.1%) and white (71.0%). The median age at testing was 63 years (IQR: 16) and the median ages of first and second cancer diagnosis were 49 (IQR: 18) and 58 (IQR: 17) years, respectively. Overall, 1406 (14.5%) were found to have PVs: 14.3% of females and 16.2% of males. The prevalence of PVs increased with the number of primary cancers (PCs) as follows, 2 PCs: 13.1% (95% CI:12.4-13.8%), 3 PCs: 15.9% (95% CI:14.0-18.0%), >4 PCs: 18.0% (95% CI:13.7-23.3%), (p < 0.01). Among patients with 2 PCs (n = 8145), differences in the prevalence of PVs by age at diagnosis were significant: 2 PCs diagnosed at an age < 50 (13.5%, 95% CI:12.0-15.1%), 1 PC diagnosed at an age < 50 (14.8%, 95% CI:13.4-16.5%), 2 PCs diagnosed at age >50 years (12.1%, 95% CI: 11.1-13.2%), (p = 0.01). PVs were most frequently identified in: BRCA2 (2.2%) BRCA1 (2.0%), CHEK2 (1.9%) and ATM (1.5%). There were also significant differences in the frequencies of PVs in BRCA1, BRCA2 and MLH1 by sex (p < 0.05). Conclusions: These data demonstrate a high frequency of germline PVs among both males and females with MPC. The frequency of PVs was higher among patients with a higher number of PCs. Differences in the prevalence of PVs by age at cancer diagnosis while significant, were not meaningful as 12.1% of individuals with 2 PCs diagnosed at age >50 years had germline PVs. Limitations include the homogenous testing population (predominately female and white) and small numbers in some patient categories. These data may aid in counseling patients with MPCs and their families as well as encourage less restrictive genetic testing of this population. Further analysis of PV frequencies by specific cancer combinations was conducted and will follow.

10501 Background: Multigene panel testing (MGPT) has identified TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes from no cancer to classic Li-Fraumeni syndrome (LFS). There is increasing recognition of variants at low allelic fraction (VAF) for TP53 in particular, which can be suggestive of post-zygotic mosaicism or aberrant clonal expansion (ACE), comprising clonal hematopoiesis of indeterminate potential (CHIP) or occult hematologic neoplasia. Distinguishing among these categories is essential because of widely different cancer risk and management implications for patients and their relatives. We report an evaluation of TP53 positive probands to determine germline versus somatic status from a cancer genetics clinic. Methods: We reviewed probands with TP53 P/LP variants by MGPT on blood (N = 83) or saliva (N = 1) samples from 2012-2019. Available VAFs were collected from commercial testing laboratories. Probands positive for a known familial variant, who met LFS testing criteria without indication of low VAF, or who carried the Brazil founder p.R337H variant were considered germline. For those with uncertain germline status, data was obtained from ancillary testing of family members, cultured skin fibroblasts, and other somatic benign or tumor tissues. TP53 variants were further categorized based on all available data. Results: Of the 84 probands, 28 (33%) had germline TP53 P/LP variants determined by above initial criteria; 18 (21%) were confirmed germline through ancillary testing. Seven (8%) individuals were classified as having constitutional mosaicism. In eleven (13%) individuals, the TP53 variants were consistent with ACE, in 9 (11%) with CHIP and in 2 (2%) with a hematologic malignancy (1 CLL, 1 NHL). Five (6%) cases could not be categorized despite ancillary testing. Fifteen (18%) probands declined any further workup. Conclusions: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, only 54% of patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism (8%) require intensified surveillance. Assessment of VAF, family member testing, and analysis of TP53 in cultured fibroblasts or other tissue samples may distinguish germline and constitutional mosaic variants from the ACE spectrum. Expanding use of MGPT will increase this clinical challenge, which may motivate the modification of lab reports to include VAF and possible non-germline explanations. The findings of this study support a framework of multiple strategies to discern true constitutional status of a TP53 P/LP variant.

Background: There is evidence that increases in germline cancer genetic testing result in higher rates of contralateral prophylactic mastectomy (CPM) in newly diagnosed breast cancer (BC) patients, even among those with negative results. Unlike carriers of BRCA pathogenic variants (PV), the risks of contralateral breast cancer (CBC) and benefits of CPM for women with PV in moderate penetrance genes are not well studied. There is a critical need to determine how to best counsel BC patients about their personal CBC risk and surgical decisions. Trial design: Newly diagnosed BC patients are randomized 1:1 to quantitative or standard post-genetic test cancer risk counseling methods by genetic counselors. Quantitative counseling includes personalized CBC risk estimates. For patients with a PV in a BC risk gene, CBC risk estimates are calculated via the “ASK2ME” decision tool (https://ask2me.org/). For those without a BC-associated PV, CBC risk estimates are calculated via a validated model “CBCRisk” (https://cbc-predictor-utd.shinyapps.io/CBCRisk/).Standard counseling does not typically include specific CBC risk estimates.Eligibility criteria: All patients over 18 with newly diagnosed invasive or in situ unilateral BC considering genetic testing at Dana-Farber/Brigham and Women’s Cancer Center are eligible. Exclusion criteria include a diagnosis of previous BC, metastatic or bilateral BC, hematologic malignancy, prior or active other malignancy, prior multi-gene panel testing, known medical or surgical contraindication to surgery and/or CPM.Specific aims: The primary aims are to 1) compare changes in patients’ personal CBC risk assessment before/after quantitative versus standard counseling; 2) determine changes in patients’ propensity to choose CPM before/after quantitative versus standard counseling. The secondary aims are to: 1) compare CPM rates; 2) determine concordance between patient and surgeon assessment of CBC risk; 3) evaluate patient genetic testing satisfaction via the Genetic Testing Satisfaction Survey administered post-counseling; 4) measure patient anxiety via the PROMIS Anxiety Survey administered pre- and post-counseling, at 6 months and 2 years; and 5) measure patient decisional regret for both undergoing genetic testing and their surgery choices at 6 months and 2 years; all by quantitative versus standard counseling arms. Statistical methods: For aim 1, the difference between patients’ reported personal CBC risk and true risk before and after counseling will be determined. True risk will be based on the ASK2ME/CBCRisk estimates. We hypothesize that the difference between the true and estimated risk will be smaller post-counseling, and smaller in the quantitative counseling versus standard arm. Assuming an expected difference of 5% and expected standard deviation of 20%, 199 patients are needed for each arm to achieve 80% power and type I error of 5% (based on a two-sample t-test). For aim 2, to determine propensity to undergo CPM, patient responses will be assigned a numeric value: Very Unlikely (1), Somewhat unlikely (2), Unsure (3), Somewhat likely (4), Very likely (5). For each patient we will then calculate the difference in scores before/after counseling. Our hypothesis is that differences will be greater in the quantitative arm. Assuming an expected difference of 0.8 and expected standard deviation of 3, 175 patients are needed for each arm to achieve 80% power and type I error rate of 5% (based on a two-sample t-test). Accrual: Recruitment began on June 8, 2020; there are currently 9 of the target 450 patients enrolled. Funding Support: Sponsored Research Agreement with Myriad Laboratories, Inc. and a Brigham and Women’s Hospital Department of Surgery Robert T. Osteen Junior Fellowship Award. PI: Anna Weiss, aweiss5@bwh.harvard.edu, @DrAnnaWeiss Citation Format: Anna Weiss, Danielle Braun, Jill Stopfer, Daniel Desantis, Meaghan Dwan, Dillon Davis, Anjali Jha, Laura Dominici, Shoshana Rosenberg, Tari A. King, Elizabeth A Mittendorf, Mehra Golshan, Huma Q Rana, Judy E Garber. Genetic testing for all breast cancer patients (get facts) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-20-01.

1507 Background: Approximately 10% of men with advanced prostate cancer (PC) have pathogenic/likely pathogenic variants (PV) in cancer susceptibility genes and their identification may lead to targeted therapy. Genetic testing (GT) can also guide cancer surveillance and prevention for family members. While GT is recommended for men with potentially lethal PC, traditional testing models are strained, and access limited. The ProGen study examined a novel pretest model aimed at providing access to GT while promoting informed consent. Methods: Inclusion criteria were: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), diagnosis age ≤ 55 years, prior malignancy, family history suggestive of a PV and/or at oncologist’s discretion. Consented subjects from 3 sites were randomized 3:1 to video education (VE) or in-person genetic counseling (GC). Subjects who consented to GT had 67 genes analyzed (Ambry, USA) with results disclosed by telephone by a genetic counselor. Outcomes included GT uptake, PV prevalence, and survey measures of satisfaction, distress, genetics knowledge, family communication, and impact on cancer care (obtained at the time of intervention, and at 1, 4, and 12 months after result disclosure). Two-sided Fischer exact tests were used for between-arm comparisons. Results: Over a 2-year period: 662 subjects were randomized, VE or GC were completed by 604 subjects (VE: 93.1%, GC: 88.8%) of whom 596 subjects (VE:98.9%, GC:97.9%) consented to GT. To date, 591 subjects have completed GT (VE: 99.3%, GC: 98.6%). At the time of intervention, most subjects agreed or strongly agreed that their assigned arm was useful (VE: 95%, GC: 88%). Differences were not statistically significant. Notably, 84 PV were identified in 78 subjects (13.2%), with BRCA1/2 PV accounting for 32% of subjects with a positive result ( BRCA2:21, BRCA1:4). Conclusions: In this randomized trial, both novel VE and traditional GC yielded high GT uptake without significant differences in outcome measures of acceptability and satisfaction. VE enabled access to critical GT results while maintaining the core tenants of informed consent. PV were found in 13.2% of subjects, 32% of whom had BRCA1/2 PV. Analysis of collected survey data to inform strengths and limitations of VE as compared with pretest GC will be presented. Clinical trial information: NCT03328091.

659 Background: Hereditary RCCs account for 3-5% of all RCC cases. The prevalence and significance of germline PVs of RCC have not been fully characterized. Methods: We evaluated the frequency of pathogenic and likely pathogenic variants, referred to as PVs, in 1829 high-risk RCC pts who underwent targeted clinical germline testing (1-134 genes) at a commercial laboratory. PVs, including single nucleotide variants/indels/ copy number variants, were confirmed using orthogonal technology in accordance with Invitae’s standard operating practices. Actionable genes were defined as established cancer-predisposition genes that confer a higher risk for any cancer phenotype and for which enhanced screening and family genetic testing are recommended by the National Comprehensive Cancer Network. We focused our analysis on genes tested in more than 100 pts (n=93). Results: Among 1892 pts, 54.9% were male, and 68.9% were Caucasians, with median age 50 (range:1-87) years at RCC diagnosis. 11.8% (n=215) of pts had at least 2 primary RCCs, and 30.7% (n= 561) had a personal history of another cancer. The cumulative frequency of pts with PVs was 17.7%. PVs in known RCC susceptibility genes such as FH, FLCN, and SDHB were detected in 1.8% (29/1622), 1.22% (120/1634) and 0.64% (11/1727) of pts respectively. PVs in other cancer-associated genes were most frequently reported in CHEK2 (loss-of-function variants, 30/1276, 2.4%), MUTYH (19/1124, 1.7%), and BRCA2 (17/1276, 1.33%). PVs in DNA-damage repair genes (DRG) accounted for 71.8% of PVs and, overall, were detected in 12.7% of pts. Among the DRG, PVs in the homologous recombination pathway (ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RECQL4, WRN) were the most prevalent (7.8%) whereas the mismatch repair pathway (MLH1, MSH2, MSH6, PMS2) was altered in only 0.7% of pts. Of the examined cohort, 9.7% of pts had ≥1 actionable PV. In non-Caucasians, BRCA2 PVs were the most common (6/273, 2.20%). Conclusions: PVs were identified in 17.7% of RCC subjects, most of which (71.8%) were in DRG, with »10% of pts having actionable variants. Our work is concordant with known RCC susceptibility genes and potentially highlights novel risk genes that should be validated in future studies.

Transgender individuals comprise a growing patient population in genetic counseling practice. The identification of a pathogenic variant in a cancer susceptibility gene may impact a transgender person's decisions regarding hormonal and/or surgical transition. Limited scientific literature exists on specific genetic counseling needs and medical management strategies for transgender individuals. In addition, most genetic counselors have had limited experience and training in conducting genetic counseling sessions with transgender patients. In this report, we describe three cases of transgender individuals who underwent genetic counseling and testing in our clinic. All were at ≥50% risk to carry a familial BRCA1 pathogenic variant. Case 1 is a 20-year-old transgender female initiating hormonal agents. Case 2 is a 19-year-old transgender male considering surgical decisions who has a BRCA1 pathogenic variant on both sides of the family. Case 3 is a 24-year-old transgender male who had previously undergone gender-affirming mastectomy (top surgery) and is taking androgen therapy. Unique aspects of genetic testing, psychosocial counseling, and medical management of transgender individuals have arisen in the course of their care. In this report, we discuss our experiences and practices of case preparation, case management, appropriate genetic testing, and medical management such as screening, surgical decisions, and coordination of care. There is a need for more research in this area and more transgender-specific training for genetic counselors.

The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2, MSH6, MLH1, PMS2 and EPCAM. Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.

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.

Importance Patients with germline mutations in BAP1 may develop several flesh-colored melanocytic BAP1 –mutated atypical intradermal tumors (MBAITs). These tumors generally develop earlier than other BAP1–associated tumors, highlighting an important role for dermatologists in identifying and screening patients with a history suggestive of a germline mutation. Objective To describe 8 new families with germline mutations in BAP1 and provide a comprehensive review of reported cases. Design, Settings and Participants Patients were identified in an outpatient dermatology clinical setting over a 6-month period (10 mutation carriers from 8 families) and through a literature review using PubMed (205 patients). Exposures Mutations were identified through next-generation sequencing of saliva or blood samples, and RNA was extracted from fibroblasts cultured from a patient with an intronic variant to determine the impact of the mutation on the coding sequence. Main Outcomes and Measures All 215 patients were assessed for personal and/or family history and genotype. These findings were compiled and assessed for any association between genotype and phenotype. Results Overall, this study included 215 patients (108 women, 91 men, and 16 gender unspecified; median [range] age, 46.5 [10.0-79.0] years). Nine of the 10 patients who were identified in the outpatient dermatology setting were found to have MBAITs on clinical examination. Forty of 53 patients (75%) identified in the literature review who underwent total-body skin examinations (TBSE) were found to have MBAITs, suggesting a high penetrance in patients who have undergone TBSE. The most prevalent malignancies among BAP1 mutation carriers were uveal melanoma (n = 60 [28%]), mesothelioma (n = 48 [22%]), cutaneous melanoma (n = 38 [18%]), and renal cell carcinoma (n = 20 [9%]). A total of 71 unique mutations in BAP1 have been reported. Conclusions and Relevance Our results indicate that germline mutations in both coding and noncoding regions throughout the BAP1 gene can impair protein function, leading to an increased risk for several associated malignancies. Four of the 8 probands we present had no history of BAP1-associated malignancies and were assessed for germline mutations when found to have MBAITs on dermatologic examination. Dermatologists can identify patients with a high likelihood of the BAP1 cancer syndrome through personal and family history and TBSE for the presence of possible MBAITs.

Objective Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations. Patients and results We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2. Conclusions We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis.

PURPOSE OF REVIEW Paraganglioma and pheochromocytoma (PGL/PCC) are tumours of neural crest origin that can present along a clinical spectrum ranging from apparently sporadic, isolated tumours to a more complex phenotype of one or multiple tumours in the context of other clinical features and family history suggestive of a defined hereditary syndrome. Genetic testing for hereditary PGL/PCC can help to confirm a genetic diagnosis for sporadic and syndromic cases. Informative genetic testing serves to clarify future risks for the patient and family members. RECENT FINDINGS Genetic discovery in the last decade has identified new PGL/PCC susceptibility loci. We summarize a contemporary approach adopted in our programme for genetic evaluation, testing and prospective management involving biochemical monitoring and imaging for hereditary PGL/PCC. A clinical vignette is presented to illustrate our practice. SUMMARY Current estimates that up to 40% of PGL/PCC are associated with germline mutations have implications for genetic testing recommendations. Prospective management of patients with defined hereditary susceptibility is based on established guidelines for well characterized syndromes. Management of tumour risk for rare syndromes, newly defined genetic associations and undefined genetic susceptibility in the setting of significant family history presents a challenge. Sustained discovery of new PGL/PCC genes underscores the need for a practice of continued genetic evaluation for patients with uninformative results. All patients with PGL/PCC should undergo genetic testing to identify potential hereditary tumour susceptibility.

The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHx) lead to a number of inherited endocrine cancer predisposition syndromes, including familial paraganglioma/pheochromocytoma. Recent studies suggest a possible role for the SDH complex and other mitochondrial enzymes in the pathogenesis of hematological malignancy. Our aim was to search and identify pedigrees of patients affected by germline SHDx mutations treated at our institution for endocrine and other tumors, and seek to identify cases of hematological malignancy. We also analyzed cancer genome databases for reported cases of SDHx mutations outside of endocrine neoplasms. We report of two unrelated pedigrees carrying SDHx mutations with members affected by lymphomas. Sequencing data revealed one case of chronic lymphocytic leukemia with a SDHB mutation. This novel set of observations demonstrates the need for collaborative databases of patients with endocrine cancers with SDHx mutations, and the investigation of their role in hematological (lymphoid) malignancy.

1528 Background: While small studies have supported a genetic cancer predisposition among subjects with urothelial carcinoma (UC), systematic germline evaluation of this population is lacking. Here, we report the prevalence of germline variants among subjects with UC from multiple centers completing panel-based testing at a large, commercial laboratory. Methods: 1149 UC subjects underwent germline testing of 1 to 126 genes using massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. Analysis was limited to 645 subjects who completed testing of a shared set of 42 genes. P/LP variants including single nucleotide variants/indels/ copy number variants are reported. De-identified personal and family cancer histories were evaluated. Fisher’s Exact test and the Mann-Whitney test were used to analyze categorical and continuous variables respectively. Results: Among the 645 UC subjects with 42-gene testing for any indication, median age at testing was 60 years (6-88) and 326 (51%) were female. P/LP variants were identified in 21 (50%) of the 42 genes in 98 (15%) of subjects, including Lynch syndrome genes (n = 26 [4%]), BRCA1/2 (n = 16 [2.5%]), CHEK2 (n = 15 [2.3%]), and heterozygous MUTYH (n = 12 [1.9%]). Among 18 DNA damage repair (DDR) genes assessed, 90 P/LP variants were detected in 88 subjects (12.2%). There was no significant association between presence of a DDR gene variant and age at diagnosis, gender or reported family history of UC in a first degree relative (n = 48). Among subjects with documented history of UC only without other cancers (n = 195), 24 (12.3%) had P/ LP variants, of which 23 (11.8%) were in a DDR gene. Conclusions: Germline P/LP variants were identified in 15% of UC subjects most of which (92%) were in DDR genes, including 27% in Lynch syndrome genes. PARP and T-cell checkpoint inhibitors may warrant evaluation in subjects with germline DDR mutations. Further validation in unselected UC pts is warranted to propose examining germline P/LP variants in all UC patients.

TPS343 Background: Prostate cancer (PC) is among the leading causes of cancer mortality in males. Recent studies found 8-12% of advanced PC cases may be hereditary. Germline mutations have been reported in BRCA1/2, other DNA repair genes including ATM, CHEK2, PALB2 and DNA mismatch repair genes. Genetic testing can inform treatment decisions including drug targeting, such as PARP inhibitors for men with BRCA mutations, and checkpoint inhibitors for those with pathogenic mutations in mismatch repair genes2. Discovering a pathogenic mutation associated with increased cancer risk also prompts dissemination of this information to family, where subsequent testing can lead to risk stratification and impactful opportunities for cancer screening and prevention. It is critical that men with high risk and potentially lethal prostate cancer routinely be offered genetic testing as a component of their cancer care. Genetic counseling services are limited, and more efficient services are needed. Methods: We are investigating video education prior to genetic testing compared with in-person pretest counseling with a licensed genetic counselor (GC). ProGen is an ongoing randomized trial evaluating two distinct models of cancer genetics service delivery in 450 PC cases over a two-year period. The study is conducted in collaboration with Ambry Genetics utilizing a 67-gene cancer panel. The primary aim is analysis of the proportion and type of germline mutations identified. Secondary aims include testing uptake by arm, evaluation of distress, knowledge, satisfaction with testing services, family communication, and impact on cancer care. Results are communicated by telephone with a GC. Inclusion criteria are: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), early diagnosis (≤ 55 years), prior malignancy, and/or family history potentially indicating a hereditary cancer risk. Enrollment is 74% completed at a single institution. (NCT03328091). 1 Pritchard CC, et al. Inherited DNA‐repair gene mutations in men with metastatic prostate cancer. NEJM. 2016;375:443 2 Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM . 2015;373(18):1697-1708 Clinical trial information: NCT03328091.

Background: MGPT for hereditary cancer syndromes allows for concurrent analysis of genes associated with many different cancer types. This may lead to the identification of unexpected mutations in genes with no BC link. The objective of this study was to examine the landscape of pathogenic mutations in a BC cohort who underwent MGPT, to assess if there was clinical suspicion for identified mutations and if the results would affect subjects' medical management. Methods: Retrospective review of subjects with BC seen at a single institution who underwent MGPT from 1/1/15- 5/31/18 was conducted. MGPT was defined as testing of more than the 9 genes associated with BC (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53). Deidentified pedigrees were analyzed by genetic counselors to determine whether there was clinical suspicion of the presence of the mutations using national testing guidelines or clinical diagnostic criteria. Results: Among 3044 subjects, 365 (12%) were found to have one pathogenic mutation in at least one cancer susceptibility gene. Subjects with mutations in APC I307K, moderate-penetrance BC genes (NBN, RAD50, BARD1), and MUTYH were excluded from further analysis. We identified 52 pathogenic mutations in genes not typically associated with risk for BC in 51 (2%) subjects (table 1). There was clinical suspicion for the identified mutation in 17 (33%). Table 1:Non-BC gene mutation landscape Number of MutationsClinical Suspicion (%)Lynch syndrome117 (64%)MLH110MSH221MSH632PMS254Ovarian181 (6%)BRIP1*111RAD51C40RAD51D30SHDx62 (33%)SDHA*30SDHC*32Other156 (40%)FH10HOXB13*32MITF32NF142VHL40CDKN2A21 (50%)Total5217 (33%)*Contains individuals that also have a mutation in a BC susceptibility gene Conclusion: Of 3044 BC patients who underwent MGPT, 2% were found to have a pathogenic gene mutation that would have been missed by a smaller BC gene panel. Medical or surgical management would be affected by the MGPT result in 86% of subjects. Only 6% of subjects with genetic risk for ovarian cancer had a family history of this disease. The single FH and 3 of 4 VHL mutations are only associated with disease in the biallelic state; these findings do not affect the subjects' care, but have implications for reproductive risk. The HOXB13 mutations were found in female subjects only, but would have implications for their male relatives. NF1 mutations are associated with BC risk, but were included in this analysis due to a historically distinct clinical phenotype. Only 50% of NF1+ subjects had a clinical diagnosis or family history of NF1. In all cases, cascade testing was offered to at-risk family members, allowing for cancer and reproductive risk stratification and management. This study demonstrates how comprehensive MGPT can provide a more complete and personalized cancer risk assessment for BC patients and their families. Citation Format: Culver S, Kipnis L, Stokes S, Bychkovsky B, Scheib R, Rana H, Garber J. Casting a wide net: Finding actionable results in non-breast cancer (BC) genes on multi-gene panel testing (MGPT) in a BC cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-02.

EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR–based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR–based therapy for the treatment of metastatic lung adenocarcinoma.

The majority of research on cancer genetic counseling and testing has been conducted in academic medical centers and among predominantly Caucasian cohorts. Unfortunately, underserved and minority populations who have a disproportionate burden of cancer have, historically, had limited access to and poor utilization of these services despite proven benefits of cancer risk reduction in high-risk individuals. Based on a unique co-location model that addresses this disparity gap, the Dana-Farber Cancer Institute (DFCI)'s Cancer Care Equity Program (CCEP) added a genetics arm to its Community Cancer Program (CCP), housed in a neighborhood Federally Qualified Community Health Center (FQHC) in 2013. The aim of this study was to determine clinic utilization rates, uptake, and outcomes of genetic evaluations as well as to describe the barriers to obtaining genetic testing among patients referred to the CCP. Methods: The intervention cohort consisted of patients referred to the CCP by their primary care providers (PCP) for cancer genetics counseling and testing between August 2013 and April 2017. A geneticist and a genetic counselor from DFCI's Cancer Risk and Prevention Program provided risk assessment and counseling according to the National Comprehensive Cancer Network (NCCN) guidelines. Prospective data approved by the IRB were collected on a secured REDcap database that was designed for the CCEP. Information including attendance at clinic, patient demographics, personal and family history of cancer or familial mutation, previous genetic testing for cancer, recommendation for genetic testing, uptake, and results were extracted and analyzed descriptively (JMP Pro version 12, SAS Institute Inc., Cary, NC). Results: Seventy out of 118 patients referred by PCPs attended clinic, indicating a no-show rate of 41%. Of the 70, 62 (89%) consented to research. The mean age of the study population was 43 (SD±11.6) years and 87% were women. More than half of the participants (57%) were Blacks/African Americans (Non-Hispanic-31% and Hispanic-26%), 32% were Whites (Non-Hispanic-13% and Hispanic-19%), and 8% were other races. Interpreter services, mainly Spanish, were provided for 32% of participants. The majority (76%) had Medicaid insurance, 8% had Medicare,13% had private insurance, and 3% had health safety net/free care. While not mutually exclusive, 66% of participants reported a family history of breast cancer, 32% ovarian cancer, 23% colorectal cancer, and 23% other cancers. There were two (3%) participants with a personal history of cancer, two (3%) with a presence of familial mutation among family members (BRCA 1/2), and two (3%) with prior genetic testing. Of the two who had prior testing, one had a familial mutation (APC). Overall, 43 (69%) participants were recommended for genetic testing. The most frequent reason for non-recommendation was that there was a better testing candidate in the family (53%). Another 21% were asked to clarify their family history before completing cancer risk assessment. Of the 43 who were recommended for testing, 32(74%) completed testing with nearly all (91%) testing for multigene panels. Lack of insurance coverage was the most frequent (73%) reason for not undergoing a test. Among those who completed testing, a pathogenic mutation (MUTYH) was identified in one participant (3%), while 13 (39%) had variants of unknown significance (VUS) and 18 (59%) had no mutations identified. Conclusions: Our findings highlight the need for increased knowledge of family history and utilization of cancer genetic services among underserved and minority populations. Additionally, efforts should be made to improve insurance coverage for genetic testing in high-risk underserved individuals. Further research on the clinical significance of variants of uncertain significance identified in ethnic minority populations is also advised. Citation Format: Ruth N. Akindele, Huma Q. Rana, Sarah R. Cochrane, Ludmila A. Svoboda, Christopher S. Lathan. Utilization and outcomes of cancer genetics referrals at a community cancer program [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B32.

Importance Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase ( GBA ) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations. Objective To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes. Design, Setting, and Participants The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson’s Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation. Main Outcomes and Measures The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test. Results Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers ( P = .008, log-rank test) and in heterozygotes than noncarriers ( P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes ( P = .07, log-rank test). Conclusions and Relevance Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.

Next-generation sequencing technology affords an unprecedented opportunity to analyze multiple breast cancer susceptibility genes simultaneously. With the incarnation of gene panels that combine testing for moderate- and high-penetrance genes, this technology has given birth to a paradigm shift in clinical genetic test offerings. A transformation in genetic counseling for cancer susceptibility will necessarily follow, with a shift from the traditional approach of single-gene testing to considerations of testing by multi-gene panels. At the same time, however, the opportunity to identify rare lesions underlying hereditary susceptibility has introduced new challenges. Available cancer risk estimates for genes included in panel tests may not be supported by evidence, and there is increased risk of identifying variants of uncertain significance (VUS). Management of individuals with rare pathogenic mutations may be unclear. We provide a summary of available evidence for breast cancer risks conferred by pathogenic mutations in genes commonly included in breast cancer susceptibility panels, as well as a review of limitations and counseling points.

Since its description by Li and Fraumeni over 40 years ago, Li-Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association with TP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multigene assessments of individuals at increased cancer risk, which have already begun to identify those with very little personal or family cancer history carrying germline TP53 mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention, and management. Finally, we observe how the clinical criteria for TP53 mutation screening appear to be evolving as our understanding of the impact of germline TP53 mutations continues to expand.

We sought to estimate age-specific risk of Parkinson disease in relatives of patients with Gaucher disease, who are obligate carriers of GBA mutations and who were not ascertained by family history of Parkinson disease.A validated family history of Parkinson disease questionnaire was administered to 119 patients with Gaucher disease who were evaluated at the Mount Sinai School of Medicine from 2009 to 2012; the ages of their parents, siblings, and children, history of Parkinson disease, age at onset of Parkinson disease, and ethnic background were obtained. Kaplan-Meier survival curves were used to estimate age-specific Parkinson disease penetrance among parents of patients with Gaucher disease, who are obligatory GBA mutation carriers.Two participants with Gaucher disease were affected by Parkinson disease (5.4% of those who were 60 years or older). Of the 224 informative parents of patients with Gaucher disease, 11 had Parkinson disease (4.9%). Among the parents (obligatory carriers), cumulative risk of Parkinson disease by ages 65 and 85 was estimated to be 2.2% ±2.1% and 10.9% ±7.2%, respectively.We provide useful age-specific estimates of Parkinson disease penetrance in patients with Gaucher disease and GBA heterozygous carriers for genetic counseling. Although GBA mutations may increase the risk for PD, the vast majority of patients with Gaucher disease and heterozygotes may not develop the disease. Further studies are needed to identify what modifies the risk of Parkinson disease in GBA mutation carriers.

Epidermal growth factor receptor (EGFR) activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms including constitutive activation of AKT signaling. Additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. Here we identify a transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that negatively regulate activated EGFR signaling and that can be reactivated using the combination of two FDA approved agents in both cell culture and in vivo models of the disease. In both murine models and patient derived lung adenocarcinoma samples, EGFR activation is associated with FOXO1 mislocalization and decreased KLF6 expression. Furthermore, in a Kras driven mouse model, KLF6 expression is not significantly changed whereas AKT activation seen in the Pten/Mmac1+/− heterozygous mouse model results in FOXO1 mislocalization and decreased KLF6 expression. Consistent with these findings, inhibition of AKT signaling promotes increase in nuclear FOXO1 resulting in transactivation of the KLF6 tumor suppressor gene in lung adenocarcinoma cell lines. Correspondingly, the EGFRL858R mouse model demonstrates spontaneous tumor regression when treated with the anti-EGFR based therapy, erlotinib, an FDA-approved small-molecule inhibitor of EGFR signaling. We analyzed L858R mouse tumors samples treated with erlotinib and found increased KLF6 expression following EGFR inhibition. Conversely, targeted reduction of KLF6 resulted in decreased erlotinib response in both cell culture and in vivo models of disease suggesting a direct link between KLF6 upregulation and the induction of apoptosis by anti-EGFR based therapy. Therefore, we hypothesized that acquired resistance to anti-EGFR based therapies could be overcome by restoring downstream function of the FOXO1/KLF6 transcriptional network. Here we demonstrate that an FDA-approved drug, trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restores sensitivity to AKT-driven erlotinib-resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models. Furthermore, silencing of FOXO1 blunts apoptosis mediated through combination erlotinib and TFP treatment suggesting that this transcriptional network is important for negatively regulating AKT signaling. Combined, these studies define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs with the potential for rapid clinical translation to restore chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1885. doi:1538-7445.AM2012-1885

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.