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PURPOSE: With onset of the COVID-19 pandemic, telehealth became the primary modality for health care appointments. This study examined patient experiences with and preferences for telehealth at a cancer genetic counseling clinic throughout the first 6 months of the pandemic (March-August 2020). METHODS: An anonymous survey assessed patient demographics; usage and prior experience with technology; emotional responses, technical experiences, and satisfaction with the telehealth appointment (via the Genetic Counseling Satisfaction Scale and Visit-Specific Satisfaction Questionnaire); preference for future telehealth; and recommendation of telehealth to others. RESULTS: Among 380 respondents, most were highly satisfied with the telehealth appointment (with 65.6% and 66.4% of participants completing the Genetic Counseling Satisfaction Scale and Visit-Specific Satisfaction Questionnaire, respectively). Multivariable analyses indicated several notable findings. Adjusting for relevant covariates, participants with less education felt significantly more concerned about telehealth than those with highest educational attainment. Participants age 40-69 years were generally more comfortable, relieved, and grateful that their appointment was scheduled as telehealth than were those older than 70 years. Women were marginally more relieved and grateful for telehealth appointments than men. As the pandemic progressed, significantly more participants were highly satisfied with their telehealth appointment and participants trended toward having greater preferences for future telehealth use. Most participants (78.6%) would recommend telehealth to others, although 50.8% preferred future in-person appointments. CONCLUSION: As the pandemic progressed, patients expressed increasing preferences for and satisfaction with telehealth. Service delivery models that incorporate individual patient preferences should be developed with special consideration to factors such as age, sex, and education level.

Germline risk assessment is increasing as part of cancer care; however, disparities in subsequent genetic counseling are unknown.Pan-cancer patients were prospectively consented to tumor-normal sequencing via custom next generation sequencing panel (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) inclusive of germline analysis of ≥76 genes from January 2015 through December 2019 (97.5% research nonbillable) with protocol for genetics referral. Rates of pathogenic/likely pathogenic germline variants (PVs) and downstream counseling were compared across ancestry groups (mutually exclusive groups based on self-reported race/ethnicity and Ashkenazi Jewish [AJ] heritage) using nonparametric tests and multivariable logistic regression models.Among 15,775 patients (59.6%, non-Hispanic [NH]-White; 15.7%, AJ; 20.5%, non-White [6.9%, Asian; 6.8%, Black/African American (AA); 6.7%, Hispanic; 0.1%, Other], and 4.2%, unknown), 2663 (17%) had a PV. Non-White patients had a lower PV rate (n = 433, 13.4%) compared to NH-Whites (n = 1451, 15.4%) and AJ patients (n = 683, 27.6%), p .01, with differences in mostly moderate and low/recessive/uncertain penetrance variants. Among 2239 patients with new PV, 1652 (73.8%) completed recommended genetic counseling. Non-White patients had lower rates of genetic counseling (67.7%) than NH-White (73.7%) and AJ patients (78.8%), p .01, with lower rates occurring in Black/AA (63%) compared to NH-White patients, even after adjustment for confounders (odds ratio, 0.60; 95% confidence interval, 0.37-0.97; p = .036). Non-White, particularly Black/AA and Asian, probands had a trend toward lower rates and numbers of at-risk family members being seen for counseling/genetic testing.Despite minimizing barriers to genetic testing, non-White patients were less likely to receive recommended cancer genetics follow-up, with potential implications for oncologic care, cancer risk reduction, and at-risk family members.Genetic testing is becoming an important part of cancer care, and we wanted to see if genetics care was different between individuals of different backgrounds. We studied 15,775 diverse patients with cancer who had genetic testing using a test called MSK-IMPACT that was covered by research funding. Clinically important genetic findings were high in all groups. However, Black patients were less likely to get recommended counseling compared to White patients. Even after removing many roadblocks, non-White and especially Black patients were less likely to get recommended genetics care, which may affect their cancer treatments and families.

Background Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith‐Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large‐scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Methods Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Results Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low‐level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Conclusions Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low‐level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing‐based approaches and detecting a cancer predisposition may modify treatment., In the current study, all patients presenting with Wilms tumor or hepatoblastoma undergo 11p15.5 methylation analysis. Approximately one‐third are found to have an epimutation at this locus that is detectable in peripheral blood.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

Background Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. Procedure WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. Results Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). Conclusions Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.

Women who are newly diagnosed with breast cancer may consider contralateral prophylactic mastectomy (CPM) to reduce their future risk of cancer in their unaffected breast. Pre-surgical BRCA1/2 genetic testing can provide valuable risk information to guide this choice. However, little is understood about why BRCA1/2 mutation noncarriers, who are generally not at substantially elevated risk of contralateral disease, select CPM. We examined the uptake of CPM among breast cancer patients identified as BRCA1/2 mutation noncarriers (n = 92) as part of a larger prospective study of the impact of pre-surgical BRCA1/2 testing. Data obtained from self-report questionnaires and patient medical records were used to examine associations between theoretically relevant background and psychosocial factors and BRCA1/2 mutation noncarriers’ decisions to undergo CPM. Among BRCA1/2 mutation noncarriers, 25% (n = 23) elected to undergo CPM. Psychosocial factors including a self-reported physician recommendation for CPM, greater perceived contralateral breast cancer risk, and greater perceived benefits of CPM were all significantly associated with the uptake of CPM. A sizeable minority of BRCA1/2 mutation noncarriers choose to undergo CPM after learning their mutation status through pre-surgical genetic testing. BRCA1/2 mutation noncarriers’ cognitive perceptions and social influences appear to be important in shaping their decisions regarding CPM. This work highlights the importance of several psychosocial factors in influencing patients’ surgical decisions. Future research is needed that examines the formation of BRCA1/2 mutation noncarriers’ beliefs regarding their disease and available treatment options, and that characterizes the physician-patient communication that occurs in this complex decision-making context.

Introduction Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. Methods We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. Results Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1–11.1). Conclusions Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

10508 Background: Disparities in access to germline testing for cancer patients (pts) have been demonstrated; however, disparities in post-testing care are unknown. We sought to evaluate germline findings and subsequent genetic counseling/care in cancer pts undergoing tumor-germline sequencing to explore differences by self-reported ancestry. Methods: Pan-cancer pts were prospectively consented to tumor-normal sequencing via a custom NGS panel (MSK-IMPACT) from 1/2015-12/2019 inclusive of germline analysis up to 88 genes. Germline analysis was performed as a research non-billable test in 97.5% of cases. Referral to clinical genetics service (CGS) was recommended for all pts with a new positive (likely pathogenic/pathogenic) germline variant (PV). Ancestry was defined using self-reported Federal definitions of race/ethnicity and designations of Ashkenazi Jewish (AJ) ancestry. Pts were categorized into mutually exclusive groups: AJ, White, Non-White (Asian, Black/African American, Hispanic, Other), and unknown. All pts self-identifying as Hispanic were classified as such, regardless of race. Abstracted data on germline findings and downstream CGS follow-up were compared across groups using non-parametric statistical tests. Results: Among the 15,775 pts in this cohort (59.6% White, 15.7% AJ, 20.5% Non-White [6.9% Asian, 6.8% Black, 6.7% Hispanic, 0.1% Other], and 4.2% unknown), 2663 (17%) had a PV. AJ pts had the highest rates of PV (n = 683, 27.6%), and Non-White pts had a lower proportion of PV (n = 433, 13.6%) compared to Whites (n = 1451, 15.5%), p < 0.01, with differences mostly due to increased prevalence of moderate/low penetrance variants in White and AJ pts . These findings were consistent across multiple tumor types. Prior knowledge of the PV (424/2663, 16%) was more common in Non-White (19.9%) and AJ (19.2%) than White pts (13.4%), p < 0.01. Among 2239 pts with new PV, all were referred to CGS, and 1652 (73.8%) pts were seen. Non-White pts had lower rates of completing visits (67.7%) than White (73.7%) and AJ pts (78.8%), p < 0.01, with the lowest rates occurring in Black (63%) and Hispanic (68.1%) pts. All pts without a visit (n = 587) received a close out letter including 139 pts (6.2% of pts with new PV) who had no documentation of receipt of results in the medical record. Higher rates of non-disclosure were observed in Non-White (6.7%) compared to White (5.4%) and AJ (3.4%) pts with new PV, p = 0.032; non-disclosure did not vary by gene penetrance. There was a non-significant trend towards lower rates of cascade testing at CGS in Asian and Black pts with ongoing analysis. Conclusions: Even when traditional barriers to genetic testing were minimized, Non-White pts were less likely to receive recommended cancer genetics follow-up for subsequent cancer risk counseling, with potential implications for oncological care, cancer risk reduction, and at-risk family members.

This chapter will examine the complex psychosocial aspects of pre- and post-test counseling for cancer genetic syndromes with both adult and pediatric onset. Using case examples, we will illustrate some of the many issues that cancer patients face when contemplating whether and when to undergo genetic testing.

Importance Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. Design, Setting, and Participants From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Exposure Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Main Outcomes and Measures Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Results Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. Conclusions and Relevance In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. Trial Registration clinicaltrials.gov Identifier: NCT01775072

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis.

Background Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMNs) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage. Procedure Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 to August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs. Results Twenty-five patients had at least one WB-MRI performed (range: 1–5). First WB-MRI was performed at a median age of 16 years (range: 8–25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in five patients: two were diagnosed with localized high-grade OS of the extremity and three were found to have benign osseous abnormalities after dedicated imaging (n = 5/5) and/or biopsy (n = 3/5). One patient was diagnosed with secondary OS 3 months after a normal screening WB-MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%. Conclusions Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors. Pediatr Blood Cancer 2014; 61:1440–1444. © 2013 Wiley Periodicals, Inc.

272 Background: MSK is deploying teleoncology solutions that improve the patient experience, quality of care, and enhance patient access. MSK’s teleoncology mission is to utilize digital technology as a mainstream channel for connected care across the cancer continuum. Methods: Teleoncology programs were established between Manhattan and four regional sites in support of Psychiatry, Genetic Counseling, and Supportive Care. MSK’s “Virtual Programs” delivered tele-education and tele-support to patients and caregivers in their home or place of work to prepare them for each stage of their care. Patient acceptability ratings were evaluated for quality of care, ease of use, interaction quality, and satisfaction and future use. Results: The four programs generated 7563 teleoncology visits. Virtual Programs served 3865 patients over 766 sessions. Fifty-eight percent (N = 2269) of patients participated in group education sessions (8.3±1.2 patients per session), while 41.3% (N = 1596) participated in support groups (3.2±0.3 patients per session). Overall, 60% of Virtual Program sessions were delivered to patients at home, and 20% to patients at work. Tele-genetics counseling was provided to 3516 patients. The majority of tele-genetics sessions occurred at regional sites (61.4%). Thirty-eight patients completed 159 telepsychiatry visits (4.2±5.8 visits/patient). In Supportive Care, 23 patients completed 38 visits (1.6±1.4 visits/patient). Patients saved 95 minutes of travel time per teleoncology visit. Acceptability ratings for teleoncology were collected from 1185 patients (15.7%). Ninety-one percent of patients were satisfied or extremely satisfied with their teleoncology experience, 95.6% with the information they received, 94.4% with the skill of the provider, and 86.3% with the ease of use of the teleoncology platform. Conclusions: Teleoncology offers an innovative means of providing cancer care to patients by decreasing the stress of travel, missed work, and caregiver requirements. Patients reported that teleoncology made care more accessible and allowed them to remain in their community with family support. For clinicians, teleoncology expanded patient outreach, and improved patient adherence.

Retinoblastoma (RB) has heritable and non-heritable forms. Testing patients with the heritable form of RB has identified different types of germline RB1 mutations in DNA from either all of the leukocytes in a patient’s blood sample or less often, in a subset of the leukocytes (which is called mosaicism). Unusual mechanisms such as inheritance from the paternal allele affecting disease penetrance or the involvement of other genes such as MED4 have been described. Testing patients with the non-heritable form has revealed mechanisms including promoter hypermethylation and loss of heterozygosity in RB1−/− retinoblastomas. The involvement of the MYCN oncogene has been suggested in a small subset of sporadic unilateral tumors in which the RB1 gene is not mutated. As more patients undergo RB1 genetic testing and laboratory methodologies continually improve, the realm of possible results will further expand. Patients with RB and their families should be introduced to the possible results and the potential uses, risks, and limitations prior to undergoing testing. Having contact with genetics professionals at the disclosure of results and in the future is also recommended. Genetic counselors are part of a multidisciplinary team caring for patients with RB. This chapter’s focus is on the role of genetics professionals and the challenges that clinicians face with the interpretation and complexities of germline testing for these patients.

e13118 Background: Somatic BAP1 mutations are very common in MM tumors (Bueno et al. Nat Genet 2016, Bott et al. Nature Genet 2011) and germline BAP1 mutations have also been shown to segregate in numerous families with clusters of malignancies including MM (Testa et al. Nat Genet 2011). However, the prevalence of germline BAP1 alterations in an unselected population of MM patients remains unknown. Methods: Unselected patients with MM were enrolled on a prospective trial (NCT01773655) to collect germline DNA, detailed family history, exposure questionnaires, and tumor tissue if available. De-identified germline DNA sequencing was performed to evaluate for the presence of BAP1 mutations. Patients with prespecified high-risk criteria (age < 50 yrs, no asbestos exposure, personal/family history of choroidal nevus, uveal melanoma, melanoma, or mesothelioma, or cancer in ≥ two 1st degree relatives) were contacted by Clinical Genetics and offered counseling and identified BAP1 testing. Results: 120 patietns with MM were enrolled. The majority are male (63%) with pleural mesothelioma (78%) and mostly epithelioid histology (75%). Sixty-seven percent met high-risk criteria for identified testing and 27 patients have consented for identified testing. Both deidentified and identified testing is ongoing. To date, among 17 patients tested, 3 have been identified with germline pathogenic BAP1 alterations. Two of those three patients had a personal history of an associated malignancy. Additional testing results will be reported at the meeting. Conclusions: Germline BAP1 mutations may be more common than previously thought among MM patients. Further work is needed to clarify those at high risk for germline mutation so they and their at-risk family members may receive testing and genetic counseling regarding their risk of malignancy. Additionally, ongoing work to define associations between genotype and phenotype should continue so that the full scope of diseases and risks are outlined for this new BAP1 associated cancer predisposition syndrome.

Contains fulltext : 126772.pdf (Publisher’s version ) (Closed access) Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.

Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMNs) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage.Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 to August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs.Twenty-five patients had at least one WB-MRI performed (range: 1-5). First WB-MRI was performed at a median age of 16 years (range: 8-25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in five patients: two were diagnosed with localized high-grade OS of the extremity and three were found to have benign osseous abnormalities after dedicated imaging (n = 5/5) and/or biopsy (n = 3/5). One patient was diagnosed with secondary OS 3 months after a normal screening WB-MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%.Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.

e21545Background: Lynch Syndrome (LS), an inherited cancer predisposition syndrome, is associated with a high risk of multiple cancers and requires lifelong multi-organ cancer surveillance and, in ...

1591Background: Retinoblastoma (RB) accounts for ~3% of pediatric cancer and is the most common primary intraocular malignancy. Patients with bilateral disease and about 15% of patients with unilat...

e18542 Background: Somatic BAP1 mutations are found in nearly a quarter of MM tumors and germline BAP1 mutations define a new cancer syndrome characterized by familial mesothelioma, uveal melanoma,...

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1., Author Summary Patients with dyskeratosis congenita (DC), a rare inherited disease, are at very high risk of developing cancer and bone marrow failure. The clinical features of DC include nail abnormalities, skin discoloration, and white spots in the mouth. Patients with Hoyeraal-Hreidarsson syndrome (HH) have symptoms of DC plus cerebellar hypoplasia, immunodeficiency, and poor prenatal growth. DC and HH are caused by defects in telomere biology; improperly maintained telomeres are thought to be a major contributor to carcinogenesis. In half the cases of DC, the causative mutation is unknown. By studying families affected by DC for whom a causative mutation has not yet been identified, we have discovered a homozygous germline mutation in RTEL1, a telomere maintenance gene that, if mutated, can result in HH. The mutations result in the inability of the RTEL1 protein to function properly at the telomere, and underscore its important role in telomere biology.

e12536 Background: Lynch syndrome (LS) requires a lifelong commitment to multi-organ cancer surveillance and/or prophylactic surgery. Emotional and informational support for LS patients is not readily available. Through an LS Educational Workshop (LSEW) we assessed the need and interest in an educational and support group for LS families. Methods: LS patients identified at Memorial Sloan-Kettering Cancer Center (MSKCC) were sent LSEW invitations and a pre-workshop survey. All patients underwent prior genetic counseling. Though family members could attend, only index patients completed the surveys. All attendees were asked to complete both an evaluation of the LSEW and a needs assessment regarding implementation of a support group. Results: Invitations to 213 LS patients were mailed. Of 8 potential discussion topics, the most desired were chemoprevention and cancer screening recommendations. Thus, the 1st hour of the LSEW was a didactic session by physicians on these topics and LS research. The 2nd hour was a panel on patient experiences, family communication and Q&A. Fifty-three patients (25% of those invited) and 22 family members attended. The LSEW evaluation was completed by 26 index attendees, with 88% overall satisfied or extremely satisfied. Common requests for improvement were better division of informational and support aspects, and more Q&A. Of 23 who completed the needs assessment, 73% considered an LS support group as either somewhat or extremely useful. The group was equally divided on preference for a free-flow vs topic-focused approach; 57% felt a support group would have increased utility immediately after genetic testing. An in person venue was preferred by 87% over a virtual one, and 73% preferred every 3-6 month meetings. Respondents preferred a group inclusive of gender and cancer history. Based on this, the MSKCC Lynch Syndrome Patient Advocacy Network was created in 2012 with an in-person, every 4 month meeting facilitated by a social worker. Conclusions: Following genetic counseling, there is a continued need for informational sessions and support groups for LS patients/family members. Implementation of an in-person support group is feasible and responsive to the needs of our LS population.