Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma.

BACKGROUND: Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors, with each having unique pathologic features. This study investigated the association between prospectively identified suspicious pathology (SP) and FH mutations when patients were referred for genetic testing. METHODS: This was an institutional review board-approved cohort study of patients receiving FH testing from 2008 to 2013. SP was defined as a report of HLRCC histologic features identified during a prospective pathologic assessment. The association between SP and FH mutations was analyzed. RESULTS: FH testing was performed in 29 patients with a median age of 37 years; 15 (52%) were female, and 18 (62%) were white. Pathologists reported SP from kidney tumors (11 of 18), leiomyomas (9 of 15: uterus [n = 8] and bladder [n = 1]), and metastatic tumors (3 of 6) in 23 of 39 associated specimens (59%) from 21 of the 29 patients (72%). Patients with SP were younger (35 vs 51 years; P = .010), and those with kidney tumors more often had stage pT3 or higher renal cell carcinoma than those without SP (100% vs 33%; P = .006). FH mutations were present in 8 patients with SP (38%) and in 1 patient without SP (13%; P = .37); 7 of these patients had kidney cancer (n for SP = 7), all with N1 disease. Analyzing SP by tissue type identified only SP from renal tumors as being significantly associated with positive testing for an FH mutation (P = .013). CONCLUSIONS: SP from kidney tumors was statistically associated with FH mutations. An expert pathologic assessment of renal tumors will facilitate the clinical identification of HLRCC cases, and this will result in genetic testing and targeted cancer screening for patients and at-risk family members. Cancer 2017;123:2452-58. © 2017 American Cancer Society.

Educational and Psychosocial Support Needs in Lynch Syndrome: Implementation and Assessment of an Educational Workshop and Support Group.

Few reports of educational and counseling support resources exist for Lynch syndrome (LS), a disorder requiring multi-organ cancer screening and specialized medical care throughout adult life. Here we describe the development and efficacy of two resources designed to address this need, the Memorial Sloan Kettering Cancer Center Clinical Genetics Service annual Lynch Syndrome Educational Workshop (LSEW), and a quarterly Lynch Syndrome Patient Advocacy Network (LSPAN) support group. The LSEW and LSPAN were implemented beginning in 2012. Participant survey data evaluating satisfaction, clarity, and unmet needs for each event were retrospectively analyzed and summarized using descriptive statistics. Annual LSEW attendance ranged from 53 to 75 total participants. LSEW year 1 participants indicated a need for a support group, and preferred in-person meetings at a frequency of every 3-6 months. For LSEW year 2-5 participants, >96 % reported satisfaction with the LSEW, and >82 % expressed interest in secure online support. Common themes for improvement included increased time for question and answer sessions and additional introductory genetics education. Responding LSPAN participants (n = 57 total survey responses in 11 meetings) found the meetings helpful (100 %), information clear (91 %), and presence of a genetic counselor useful (67 %). Desired discussion topics included coping with stress and anxiety, development of a support network, family communication about LS, genetic testing decisions, and bereavement. Following genetic counseling, a need exists for ongoing educational and emotional support in LS. Implementation of resources such as the LSEW and LSPAN is feasible and perceived as helpful by participants.

Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.

The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89×10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85×10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69×10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.

Identification of germline genetic mutations in patients with pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. METHODS: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. RESULTS: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). CONCLUSIONS: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.

Rare de novo germline copy-number variation in testicular cancer.

Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.

Community-based asthma education.

OBJECTIVES: Objectives: The authors studied the impact a community hospital-based asthma education (AE) program had on asthma understanding, healthcare utilization, and estimated costs. STUDY DESIGN: Prospective observational study. METHODS: Every self-selected enrollee in Ellis Hospital's AE program from April 1, 2011, to December 31, 2015, was captured using quality assurance data. Significant changes comparing individual progress were evaluated using 2-tailed paired t tests using SPSS software. Care utilization was measured 1 year before and after AE. Asthma control was evaluated with Asthma Control Test (ACT) scores. The average charges for emergency department (ED) visits and asthma admissions were used to estimate cost impact. RESULTS: In total, 574 patients of all ages (mean age = 30 years) were seen over the study period. Participants reported better controlled asthma (mean pre-AE ACT score = 14; mean post-AE ACT score = 19; P <.001). Individuals also demonstrated increased asthma knowledge (mean pre-AE knowledge score = 10; mean post-AE score = 13; P <.001). In the 12 months prior to education, there was a mean of 1.1 ED visits and 0.16 inpatient admissions per AE participant. In the 12 months following education, ED visits dropped to a mean of 0.4 visits and admissions to 0.06 per individual (P <.001). We estimated that the program decreased ED charges for this study cohort by about $600,000 and inpatient charges by about $230,000. CONCLUSIONS: Our data suggest that patient AE efforts at the community level are associated with better knowledge of asthma, decreased symptoms, and increased quality of life. The use of expensive resources also was favorably impacted.

Outcome of genetic evaluation of patients with kidney cancer referred for suspected hereditary cancer syndromes.

OBJECTIVE: To analyze patients with kidney cancer referred for evaluation at a high-volume genetics service at a comprehensive cancer center and identify factors associated with positive tests for hereditary cancer syndromes. METHODS: A retrospective review of patients referred to the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center was performed, and patients with a personal history of kidney cancer were identified. Patient and disease characteristics were reviewed. In all, 4 variables including age at diagnosis of kidney tumor, presence of syndromic manifestations, family history of kidney cancer, and number of primary malignancies were evaluated for association with positive test results in 2 groups: patients tested for renal cell carcinoma syndromes and Lynch syndrome. Guidance for genetic testing strategy in patients with kidney cancer is provided. RESULTS: Between 1999 and 2012, 120 patients with a history of kidney cancer were evaluated by the Clinical Genetics Service. The mean age at kidney cancer diagnosis was 52 years (interquartile range: 42-63), with 57% being women. A family history of kidney cancer was reported by 39 patients (33%). Time between diagnosis of first cancer and genetic consultation was <1 year in 54%, 2 to 5 years in 23%, and>5 years in the remaining 23%. Overall, 95 patients were tested for genetic abnormalities with 27 (28%) testing positive. Testing for renal cell carcinoma (RCC)-related syndromes was performed on 43 patients, with 13 testing positive (30%). Lynch syndrome testing was positive in 9 patients (32%) after 28 were tested. In RCC-associated syndromes, young age of diagnosis was associated with positive test results. Conversely, syndromic manifestations and increasing number of primary malignancies were associated with positive Lynch testing. CONCLUSIONS: The discovery of inherited kidney cancer syndromes has provided a unique opportunity to identify patients at increased risk for cancer. Factors associated with positive genetic testing are unique to different syndromes. These data suggest that in kidney cancer patients evaluated for hereditary cancer syndromes, young age is associated with diagnosis of RCC syndromes, whereas syndromic manifestations and multiple primaries are found in Lynch syndrome. These results, along with clinical awareness, may be useful for practicing urologists to select patients with kidney cancer to refer for genetic counseling.

Increasing influenza vaccination in New York City taxi drivers: A community driven approach.

The Healthy People 2020 influenza immunization goal is 80% for non-institutionalized adults 18-64. However, vaccination rates remain stubbornly low. Culturally tailored approaches to communities with poor vaccine uptake are necessary. Taxi drivers are at risk for influenza and its complications, could serve as vectors for influenza infection, and could be an effective vaccination target to enhance herd immunity of the urban population. To the best of our knowledge, this is the first study related to influenza vaccination among taxi drivers. The NYC Taxi Network surveyed a convenience sample of 53 taxi drivers to understand vaccination barriers. Only 17% had been vaccinated. Results informed a pilot tailored workplace intervention, which resulted in vaccinations for 44% of unvaccinated drivers. The study revealed that older drivers were more likely to be vaccinated than younger drivers, while the most common barrier to immunization was that drivers thought vaccination was 'not necessary'.

Absence of loss of heterozygosity of BRCA1 in a renal tumor from a BRCA1 germline mutation carrier.

BRCA1 functions as a tumor suppressor gene and germline and somatic mutations in this gene have been shown to be associated with many types of cancer. We report the first tumor study of renal cell carcinoma in a carrier of the deleterious BRCA1 mutation-c.68_69delAG.

Prevalence of HOXB13 mutation in a population of Ashkenazi Jewish men treated for prostate cancer.

We performed a retrospective analysis of germline DNA samples from Ashkenazi Jewish men and a comparison group of non-Ashkenazi men treated for prostate cancer at our institution to determine the prevalence of HOXB13 G84E mutation in prostate cancer patients of Ashkenazi Jewish heritage, an ethnic group common to the New York City area. Patients were genotyped for G84E using a TaqMan assay (Applied Biosystems). Positive cases were confirmed using Sanger sequencing. Median age at prostate cancer diagnosis was 68 years for 889 Ashkenazi Jewish patients, 64 years for 920 non-Ashkenazi Jewish patients. The median follow up was 9 years for Ashkenazi Jewish patients and 8.8 years for non-Ashkenazi Jewish patients. Only 4 patients were found to be heterozygous carriers of G84E. They were all of non-Ashkenazi Jewish ancestry and were diagnosed at 70, 66, 78, and 49 years of age. Two of them presented with high-risk prostate cancer. The prevalence of G84E in the non-Ashkenazi sample was 0.4%. HOXB13 G84E mutation was not observed in prostate cancer patients of Ashkenazi Jewish ancestry treated at our institution. Screening for G84E, therefore, may be unnecessary in Ashkenazi Jewish men if these results are validated by other studies.

Assessment of SLX4 Mutations in Hereditary Breast Cancers.

BACKGROUND: SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers. METHODS AND RESULTS: To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65-1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so. CONCLUSION: Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.

A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.

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.