Type Of Germline Mutation Research Articles

Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months). The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

High rates of the SDHB p.Arg46Gln pathogenic variant predisposes New Zealand Māori to phaeochromocytoma/paraganglioma.

Phaeochromocytomas (PCC) and paragangliomas (PGL; together PPGL) are rare tumours of the adrenal medulla or extra-adrenal paraganglia. They may secrete catecholamines with significant cardiovascular effects. Management of PPGL is predominantly surgical, despite the anaesthetic risks related to potential haemodynamic instability. Meticulous pre-treatment and intra-operative management are required to improve cardiovascular outcomes. There are limited local data regarding the incidence of PPGL and the clinical characteristics of individuals diagnosed with these tumours in New Zealand. We undertook a retrospective study investigating the local practice and patient characteristics with an additional focus on intra-operative haemodynamic stability and post-operative outcomes. Electronic patient records were searched for individuals with a diagnosis of PPGL. Clinical records and electronic databases were interrogated for pre-operative, intra-operative and post-operative data points. Particular attention was paid to rates and types of germline mutations, intra-operative haemodynamic stability and post-operative renal and cardiovascular outcomes. We identified 49 individuals with PPGL, of whom 34 were from the local area. This gave a local incidence of PPGL of around five cases per million people per year. Māori were significantly over-represented in our cohort, with this being in part due to high rates of the SDHB R46Q mutation. Over 95% of our cohort met pre-specified pre-operative blood pressure parameters. Intra-operative monitoring revealed a tendency to hypotension, but this did not translate into adverse post-operative outcomes, which were infrequent. Māori were over-represented due to high rates of germline SDHB R46Q mutations. There were few post-operative adverse outcomes in this contemporary cohort.

DNA damage repair (DDR) germline mutations (GMs) in pancreatic ductal adenocarcinoma (PDAC): A mono-institutional retrospective study.

10587 Background: GMs in DDR genes, in particular BRCA1/2, are associated with increased risk of cancer, including PDAC. Their identification is crucial for the clinical relevance, the best treatment choice, and the family implications in cancer prevention. However, there are few data regarding the epidemiology and the prognostic role of DDR GMs in PDAC patients (pts). The aim of our study is to determine the prevalence of DDR GMs, their correlation with clinicopathological features and their prognostic role. Methods: Unselected PDCA pts, assessed by BRCA1/2 GM analysis or multigenic panel at our Institution, were retrospectively analyzed. We divided the overall population into three groups based on GMs: pts with pathogenic variants (PVs), pts with variants of uncertain significance (VUS) and pts with no alterations. Clinicopathologic characteristics and treatment data were collected. The incidence of DDR GMs variants and their association with overall survival (OS) were evaluated. Univariate and multivariate analyses for OS were performed. Results: From September 2019 to August 2021, 200 PDAC pts were tested for DDR GMs: all pts were evaluated for BRCA 1/2; 140 pts were tested for further DDR GMs by a multigenic panel. Twenty-five pts (12.5%) had PVs, 45 (22.5%) pts had VUS and 130 (65%) pts had no GMs. BRCA 1-2 PVs were found in 10 pts (5%). Out of 91 pts with metastatic disease, the rate of PVs BRCA1/2 was 8.8%. Among 140 pts tested with multigenic panel, further PVs included: 7 (5%) ATM, 5 (3.6%) MUTYH, 1 (0.7%) TP53, 1 (0.7%) BARD1, and 1 (0.7%) MSH6. The most frequent VUS were: CHECK2 (5%), APC (3.6%), ATM (3.6%) and BRCA2 (3.6%). Regarding cancer family history, a statistically significant difference was reported between the 3 group (76% in PV pts, 82% in VUS pts and 60% in pts with no GMs; p 0.01). No difference was found concerning age (p 0.69), stage at diagnosis (p 0.31) and platinum-exposure (p 0.27). Out of 189 evaluable pts, median OS was 23 months. A significant difference in OS was observed in the 3 groups (30 months in PVs pts, 14 months in VUS pts and 24 months in pts with no GMs, p 0.0006). No factor, including the presence or the type of GMs, age, stage and family history, was significantly associated with OS at the multivariate analysis. Conclusions: In our study, we observed a high incidence of DDR GMs PV (12.5%), beyond BRCA 1/2, regardless of age, stage and family history. Despite retrospective nature of our analysis, small population, and single-institution evaluation, our findings confirm the importance of genetic testing for BRCA1/2 and, where available, of a multigenic test in all PDAC pts, due to the therapeutic implications and cancer risk prevention in patients relatives. The prognostic role of DDR GMs and the impact of VUS remain unclear.

KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.

Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations. Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using alogistic regression model adjusting for genetic background (top ten principal components). In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression. Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.

Clinical presentation, genotype\u2013phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel\u2013Lindau syndrome

PurposeData regarding the clinical management and follow-up of pancreatic neuroendocrine tumors (PanNETs) associated with Von Hippel–Lindau (VHL) syndrome are limited. This study aimed to assess clinical presentation, genotype–phenotype correlations, treatment and prognosis of PanNETs in a series of VHL syndrome patients.MethodsRetrospective analysis of data of patients observed between 2005 and 2020.ResultsSeventeen patients, including 12 probands and 5 relatives (mean age 30.8 ± 18.4; 7 males), were recruited. PanNETs were found in 13/17 patients (77.5%) at a median age of 37 years: 4/13 (30.7%) at the time of VHL diagnosis and 9 (69.3%) during follow up. Six (46.1%) PanNET patients underwent surgery, whereas seven were conservatively treated (mean tumor diameter: 40 ± 10.9 vs. 15 ± 5.3 mm respectively). Four patients (30.7%) had lymph node metastases and a mean tumor diameter significantly larger than the nonmetastatic PanNETs (44.2 ± 9.3 vs. 17.4 ± 7 mm, p = 0.00049, respectively). Five (83.3%) operated patients had stable disease after a median follow up of 3 years whereas one patient showed liver metastases. Six (85.7%) non-resected PanNETs were stable after a median follow-up of 2 years, whereas one patient developed a new small PanNET and a slight increase in diameter of a pre-existing PanNET. No correlation was found between the type of germline mutation and malignant behavior of PanNETs.ConclusionsPanNETs are a common disease of the VHL syndrome and can be the presenting feature. Tumor size rather than genetic mutation is a prognostic factor of malignancy.

Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.

The prevalence of germline mutations in patients with biliary tract carcinoma (BTC) remains unclear. Here, we investigated the prevalence and types of germline mutations in patients with BTC. We reviewed 269 patients with pathologically proven BTC and collected clinical characteristics, including medical and family histories. Additionally, we evaluated germline variants in 21 genes associated with hereditary predisposition for cancer by targeted sequencing in patients meeting ≥1 of the following criteria: 1) hereditary breast and/or ovarian cancer (HBOC) testing criteria modified for BTC, 2) Revised Bethesda Guidelines (RBGs) modified for BTC (modified RBG), 3) familial BTC criteria, or 4) young BTC criteria. Among the 269 patients, 80 met at least one criterion. Three pathogenic mutations in three patients were identified: two in BRCA2 and one in BRCA1. Among the 16 patients meeting modified HBOC testing criteria, 2 harbored germline BRCA2 mutations, and 1 harbored a germline BRCA1 mutation. However, no mutation in mismatch-repair genes were detected, despite 63 patients meeting modified RBG screening criteria and 18 qualifying as young BTC patients. We detected high prevalence of pathogenic germline mutations in BRCA1/2 and none in mismatch-repair genes in BTC patients following enrichment according to family or medical history in this study.

Distinctive low epidermal nerve fiber density in schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.

Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro‐genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age‐ and gender‐matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in schwannomatosis patients was age‐independent. Paired t‐test revealed no difference between the NF2‐IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P < 0.0001). In addition, the difference between the IEND of our patients and the 5% lowest normative reference IEND was highly significantly larger in schwannomatosis patients than in NF2 patients (P < 0.0001). IEND of our patients did not correlate with neither the presence nor types of germline mutations in neither the NF2 nor the LZTR1 gene. In conclusion, schwannomatosis patients have marked low IEND which provides a major parameter for diagnosis and differential diagnosis.

Abstract 3428: The landscape of germline mutations in Chinese patients with solid tumor

Abstract Background: Germline mutations harbored by cancer patients can be passed from parents on to offspring, which increases the tumor risk in offspring as well. Therefore, investigating the germline mutations in cancer patients has important clinical implications for treatment selection and familial cancer risk assessment. Methods: FFPE tumor and matched blood samples were collected from 3645 Chinese patients with solid tumors for next generation sequencing analysis. The NGS panel targeted 450 cancer genes, 47 of these genes were tumor inheritance susceptibility genes that were mentioned by NCCN guidelines. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions were assessed. Results:Germline mutations were identified in 241 of 3645 Chinese patients with solid tumor (6.6%). The patients with germline mutations included 137 males and 104 females with a median age of 54. Tumor types with higher frequency of germline mutations were: ovarian cancer (22.0%), breast cancer (13.4%), pancreatic cancer (9.9%), cholangiocarcinoma (8.6%), small intestinal cancer (8.6%), colorectal cancer (8.6%), soft tissue sarcoma (6.3%), uterine Cancer (5.9%), gastric cancer (5.8%) and bone cancer (5.1%). The distribution of germline mutations were 14.1% in BRCA1, 13.7% in BRCA2, 10.8% in SPINK1, 9.1% in ATM, 5.8% in RAD50, 4.6% in PALB2, 3.7% in BARD1 and FANCA, 3.3% in MSH6 and 2.9% in MLH1, respectively. The types of germline mutations were SNVs and short Indels, but no long Indels, CNV, gene rearrangements or fusions were observed. The percentage of patients with a family history was 27.4%, without family history was 52.7%, unknown was 19.9%. Conclusions:Our data revealed that germline mutations occurred in 6.6% of Chinese solid tumor patients. Gynecological tumor, gastrointestinal tumor, bone and soft tissue tumor are the most common types of tumors that harbored germline mutations. The most common mutant genes were HRD (64.5%) and MMR (10.5%) related genes. More than 50% patients with germline mutations had no family history, which suggests the importance of germline mutations detection for all solid tumor patients to verify if there is a risk of genetic transmission to offspring. NGS based panel sequencing showed the advantage of identifying solid tumor patients with germline mutations, and provided the information of familial cancer risk assessment and guided the precise cancer treatment options. Citation Format: Juming Li, Yongzhong Wei, Xiaoqian Chen, Angen Liu, Junping Shi, Jinwei Hu, Ming Yao. The landscape of germline mutations in Chinese patients with solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3428.

Abstract 2508: Genomic alterations of BRCA1/2 genes in Chinese solid tumor patients

Abstract Background: BRCA1 and BRCA2 are tumor suppressor genes that play an important role in DNA repair pathways. Germline mutations in BRCA1 and BRCA2 contribute to a significant number of familial and hereditary breast and/or ovarian cancers. Additionally, BRCA 1/2 alterations induce sensitivity to poly ADP ribose polymerase inhibitors (PARPi). Therefore, the detection of BRCA 1/2 mutations in solid tumor patients is essential to predict the sensitivity to PARPi therapy. Methods: FFPE tumor and matched blood samples of 5269 Chinese patients with solid tumor were collected for next generation sequencing (NGS) based assay. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions in selected genes were assessed. Results: Three hundred patients with BRCA1/2 mutations were identified in 5269 Chinese patients with solid tumor. The patients included 177 males and 123 females with a median age of 58. Highest yields of BRCA1/2 mutations were found in patients with ovarian (24.5%) and breast (12.3%) cancers. BRCA1/2 mutations were also identified in gastric cancer (8.9%), cholangiocarcinoma (8.8%), colorectal cancer (7.1%), esophageal cancer (6.1%), gallbladder cancer (5.1%), lung cancer (4.7%), soft tissue tumor (4.1%) and pancreatic cancer (4.0%). SNVs and short Indels (84.9%) were the most common variant types of BRCA1/2, while the percentages of gene rearrangements and fusions, CNV and long Indels were 12.0%, 1.6% and 1.5%, respectively. Among patients with BRCA1/2 mutations, 224 (74.7%) patients harbored somatic mutations, 73 (24.3%) patients harbored germline mutations, 3 (1.0%) patients harbored both somatic and germline mutations. Interestingly, all of the variant types of germline mutations were SNVs and short Indels. The mutation sites were distributed in the full length of BRCA1/2 genes. No hot spot mutation was observed. Conclusions: Our data revealed that BRCA1/2 mutations occurred in 5.7% of Chinese patients with solid tumor. NGS targeted sequencing provides comprehensive and accurate information of BRCA1/2 mutations. Beyond ovarian and breast cancers, BRCA1/2 mutations could be detected in other solid tumors, which suggests potential clinical benefits from PARPi therapy. Citation Format: Junjian Wang, Lingxiang Liu, Bin Ni, Xiaoqian Chen, Ling Li, Junping Shi, Jierong Chen, Ming Yao. Genomic alterations of BRCA1/2 genes in Chinese solid tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2508.

Genetic counseling processes and outcomes among prostate cancer patients (ProGen).

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.

A multi-gene panel study in hereditary breast and ovarian cancer in Colombia.

Germline mutations in BRCA1 and BRCA2 account for approximately 50% of inherited breast and ovarian cancers. Three founder mutations in BRCA1/2 have been reported in Colombia, but the pattern of mutations in other cancer susceptibility genes is unknown. This study describes the frequency and type of germline mutations in hereditary breast and/or ovarian cancer genes in a referral cancer center in Colombia. Eighty-five women referred to the oncogenetics unit of the Instituto de Cancerologia Las Americas in Medellin (Colombia), meeting testing criteria for hereditary breast and ovarian cancer syndrome (NCCN 2015), who had germline testing with a commercial 25-gene hereditary cancer panel, were included in the analysis. Nineteen patients (22.4%) carried a deleterious germline mutation in a cancer susceptibility gene: BRCA1 (7), BRCA2 (8), PALB2 (1), ATM (1), MSH2 (1) and PMS2 (1). The frequency of mutations in BRCA1/2 was 17.6%. One BRCA2 mutation (c.9246dupG) was recurrent in five non-related individuals and is not previously reported in the country. Seventeen mutation-carriers had a diagnosis of breast cancer (median age of diagnosis of 36 years) and two of ovarian cancer. All BRCA1 mutation-carriers with breast cancer had triple negative tumors (median age of diagnosis of 31 years). Variants of unknown significance were reported in 35% of test results. This is the first report of a multi-gene study for hereditary breast and/or ovarian cancer in a Latin American country. We found a high frequency and a wide spectrum of germline mutations in cancer susceptibility genes in Colombian patients, some of which were not previously reported in the country. We observed a very low frequency of known Colombian founder BRCA1/2 mutations (1.2%) and we found mutations in other genes such as PALB2, ATM, MSH2 and PMS2. Our results highlight the importance of performing multi-gene panel testing, including comprehensive BRCA1/2 analysis (full gene sequencing and large rearrangement analysis), in high-risk breast and/or ovarian cancer patients in Colombia.

PD59-03 GROWTH KINETICS IN VON HIPPEL-LINDAU-ASSOCIATED RENAL TUMORS: DEFINING THE INFLUENCE OF GERMLINE MUTATION TYPE

You have accessJournal of UrologyKidney Cancer: Localized: Active Surveillance1 Apr 2017PD59-03 GROWTH KINETICS IN VON HIPPEL-LINDAU-ASSOCIATED RENAL TUMORS: DEFINING THE INFLUENCE OF GERMLINE MUTATION TYPE Mark Ball, Shawna Boyle, Kiranpreet Khurana, Rabindra Gautam, Gennady Bratslavsky, W. Marston Linehan, and Adam Metwalli Mark BallMark Ball More articles by this author , Shawna BoyleShawna Boyle More articles by this author , Kiranpreet KhuranaKiranpreet Khurana More articles by this author , Rabindra GautamRabindra Gautam More articles by this author , Gennady BratslavskyGennady Bratslavsky More articles by this author , W. Marston LinehanW. Marston Linehan More articles by this author , and Adam MetwalliAdam Metwalli More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2631AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal cell carcinoma develops in 25-60% of patients von Hippel-Lindau (VHL), which is characterized by germline mutations in the VHL gene. The paradigm for treating renal tumors in VHL includes active surveillance for lesions less than 3 cm, and surgical resection for lesions greater than 3 cm. Knowledge of growth rates for renal lesions in VHL guide surveillance schedules. While the risk of developing RCC is related to VHL genotype, it is unknown if VHL genotype can influence tumor growth rate. We sought to characterize growth rate for VHL-associated renal tumors and to determine if the type of germline mutation in VHL influences tumor growth kinetics. METHODS Patients with solid, enhancing renal tumors with at least 3 cross sectional imaging studies and known germline mutation status were retrospectively reviewed. In patients with multiple index lesions, all lesions were analyzed. Renal tumor size was measured as the largest single-dimension diameter. Growth rates were calculated using linear regression. Germline mutations were categorized into missense, partial deletion, frameshift, deletion, splice donor, amino acid insertion, and splice acceptor. The effect of germline mutation type on renal tumor kinetics was assessed with the Wilcoxon-ranksum or Kruskall Wallis tests. RESULTS A total of 246 tumors in 161 patients and 1341 time-point measurements were included for analysis. Median growth rate for the entire cohort was 3.5 mm (interquartile range 2.4-5.1 mm). Median growth rates were similar for all mutation categories: 3.4 mm for missense (n=111), 3.5 mm for partial deletion (n=71), 3.2 mm for nonsense (n=28), 4.5 mm for frameshift (n=16), 2.5 mm for deletion (n=8), 3.4 mm for splice donor (n=4), 3.9 mm for amino acid insertion (n=3), and 4.9 mm for splice acceptor (n=3) (Figure 1). There was no difference in growth rates between missense and non-missense tumors (p=0.1) CONCLUSIONS The majority of VHL-associated renal tumors have a growth rate of less than 5 mm per year. Where no association was identified between germline mutation type and single-dimension VHL renal tumor growth kinetics, further study is needed to determine the impact of somatic mutations on tumor development and growth kinetics. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1133-e1134 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Mark Ball More articles by this author Shawna Boyle More articles by this author Kiranpreet Khurana More articles by this author Rabindra Gautam More articles by this author Gennady Bratslavsky More articles by this author W. Marston Linehan More articles by this author Adam Metwalli More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil.

BackgroundHereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil.MethodsTwenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern.ResultsNo evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents.ConclusionThis is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study.

Barrett’s esophagus in the patients with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is caused by germ line mutations in the APC gene. Barrett's esophagus (BE) and Barrett's adenocarcinoma are intestinal type lesions of the esophagus characterized by an early loss of heterozygosity at the APC locus. We hypothesized that patients with FAP are at risk for the early development of BE due to the inherited mutations in the APC gene (haploinsufficiency). Upper gastrointestinal (UGI) tract biopsies from 36 patients with FAP were reviewed to determine the incidence and characteristics of BE in these patients. Twenty-four patients were confirmed carriers of a deleterious germline APC mutation. The other 12 patients were from FAP families with known APC gene mutations and had clinical manifestations of FAP. The control group consisted of patients who did not have a personal or family history of FAP undergoing UGI endoscopic examination in our institution over a 30 month period of time. The difference in expression of Wnt pathway proteins (APC, β-catenin, E-cadherin and cyclin D1) in BE between BE(+)/FAP(+), BE(-)/FAP(+) and age-matched BE(+)/FAP(-) groups was studied using immunohistochemistry. BE was found in 6 of 36 (6/36 or 16%) patients with FAP and in 266 of 1662 patients (16%) in the control group of symptomatic patients. The average age at the first diagnosis of BE in FAP patients was 37.8 versus 57.5 years in the control group (sporadic BE). When compared to age matched BE(+)/FAP- group (7/334), patients with FAP had a significantly (p = 0.005843, odds ratio 9.2; Fisher exact test) higher incidence of BE. Both classic FAP and attenuated FAP phenotypes were associated with BE .Two types of germ line mutations in APC gene were identified in BE(+)/FAP(+) patients: Five patients had 2-base deletion in exon 4 (426delAT) and one patient had 4-base deletion in exon 15 (3202del4). No difference in Wnt signaling pathway proteins expression was detected between BE(+)/FAP(+) and the age matched group of patients with sporadic BE (BE(+)/FAP(-)). Patients with FAP appear to have increased risk for the development of BE, which on average develops some 20 years earlier than in patients without FAP. This association needs to be taken in account when caring for the patients with FAP.

Abstract IA18: Large-scale familial whole genome sequencing to evaluate genetic risk.

Abstract Whole genome sequencing (WGS) technology and analysis is quickly approaching the stage of development where it can become a medically recognized procedure for prognostics as well as diagnostics. Critical to the development of medical-grade whole genome sequencing is the ability to recognize and minimize technological and biological variation in WGS data. The Inova Translational Medicine Institute (ITMI) has completed a study that generated 1500 whole genome sequences in 15 months and recently launched a study that will generate 20,000 WGS over the next two years. The 1500 sequenced genomes were from individuals from 53 countries, representing four major ancestral groups and many minor sub-groups. ITMI used these data to generate a database of ancestral-specific variants. This database can be used to identify single nucleotide variants in patients with a specific ancestral background as ancestral-specific sequences instead of mutations. This ancestral information was applied to the 487 cancer genes identified in the Wellcome Trust Sanger Institute's Cancer Gene Census, in an attempt to identify germline mutations in these genes, in our cohort of 1500 participants. The result of this analysis identifies the incidence and type of germline mutations in various ethnic groups. The ethical question that remains is what to do with incidental finding of this type as medical whole genome sequencing becomes a common tool in the practice of medicine. Citation Format: Joseph Vockley, Ramaswamy Iyer, Kathi Huddleston, John Niederhuber. Large-scale familial whole genome sequencing to evaluate genetic risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA18.

VHL Frameshift Mutation as Target of Nonsense‐Mediated mRNA Decay in Drosophila melanogaster and Human HEK293 Cell Line

There are many well-studied examples of human phenotypes resulting from nonsense or frameshift mutations that are modulated by Nonsense-Mediated mRNA Decay (NMD), a process that typically degrades transcripts containing premature termination codons (PTCs) in order to prevent translation of unnecessary or aberrant transcripts. Different types of germline mutations in the VHL gene cause the von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome with a marked phenotypic variability and age-dependent penetrance. By generating the Drosophila UAS:Upf1D45B line we showed the possible involvement of NMD mechanism in the modulation of the c.172delG frameshift mutation located in the exon 1 of Vhl gene. Further, by Quantitative Real-time PCR (QPCR) we demonstrated that the corresponding c.163delG human mutation is targeted by NMD in human HEK 293 cells. The UAS:Upf1D45B line represents a useful system to identify novel substrates of NMD pathway in Drosophila melanogaster. Finally, we suggest the possible role of NMD on the regulation of VHL mutations.

The Occurrence and the Type of Germline Mutations in the RET Gene in Patients with Medullary Thyroid Carcinoma and Their Unaffected Kindred's from Central Poland

We aimed to investigate the occurrence and types of pathogenic mutations in the RET gene in patients with MTC of the Central Poland population and in their relatives. DNA was extracted from the peripheral blood lymphocytes of a total of 330 persons, including 235 MTC patients and 95 of their unaffected kindred's. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by PCR and sequenced. Sixty-seven people were found to carry pathogenic, germline mutations in the RET gene. In exon 10, C609F, C609R and C609Y (3 families), C618G, C618F (2 families), and C620G (4 families) mutations were identified. In exon 11, C634R (8 families) and C649L mutations (1 patient) were found. Five families carried Y791F mutation in exon 13. One patient with PTC revealed the presence of a Y791F mutation. In 3 families, exon 14 of the RET gene harbored the following mutations: V804L (1 patient), E819K (1 patient) and R844Q (1 patient). In 1 family, the S891A mutation was identified in exon 15, 3 families were found to carry mutations in exon16, R912P in 1 family and M918T in 2 families.In summary, of the 235 patients affected by MTC, 46 (19.6%) carried pathogenic RET gene mutations, 1 patient with RET mutation had kidney carcinoma, and 1 had PTC. The results show the occurrence of a variety of mutations prevalent in patients with MTC in the population of Central Poland. These results may contribute to a better diagnosis of medullary thyroid carcinoma.

N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC)

N-acetyltransferase (NAT) 2 is an essential polymorphic enzyme involved in the metabolism of various xenobiotics, including potential carcinogens. The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes. Highly penetrant germline mutations in mismatch repair (MMR) genes are the cause of the disease in hereditary nonpolyposis colorectal cancer (HNPCC). There is no strict correlation between the type of germline mutation in MMR genes and the HNPCC phenotype, but age of tumor onset (AO) in HNPCC has been associated at least in part with different variants in apoptosis-related genes. To clarify the potential modifying role of the NAT2 acetylator status in HNPCC, we performed a multicenter study in 226 individuals with colorectal cancer carrying exclusively pathogenic germline mutations in MSH2 or MLH1. We did not observe any significant difference in the NAT2 acetylator status frequency between HNPCC patients and 107 healthy controls ( P=0.156), and between MLH1 and MSH2 mutation carriers ( P=0.198). Multivariate Cox regression analysis revealed that male patients had a significantly increased risk to develop CRC compared to females during any interval ( P=0.043), while the NAT2 acetylator status ( P=0.447) and the mutated gene ( MLH1 or MSH2) ( P=0.236) were not risk factors for AO. The median AO in HNPCC patients was 39 years in patients with RA as well as with SA status ( P=0.347). In MLH1 mutation carriers, the median AO was 38 years in RA and 36 years in SA status patients ( P=0.901), whereas in MSH2 mutation carriers, the median AO was 39 years in RA and 42 years in SA status patients ( P=0.163). Log-rank test revealed a significantly lower age of CRC onset in male compared to female HNPCC patients ( P=0.0442). These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on AO in HNPCC-associated CRC.

Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil.

5‐Fluorouracil (5FU) is most commonly used in chemotherapy for human malignancy. Over 80% of administered 5FU is metabolically degraded by dihydropyrimidine dehydrogenase (DPD), a primary and rate‐limiting enzyme in the 5FU metabolic pathway. A DPD‐deficient phenotype among cancer patients, which has posed a serious problem in 5FU‐based chemotherapy, was reported to be in part ascribed to germline mutations in dihydropyrimidine dehydrogenase (DPYD) gene. Therefore, we for the first tune examined the frequencies and types of germline mutations in the DPYD gene among a total of 107 Japanese cancer patients and healthy volunteers. Of 214 alleles examined among them, 181 alleles were of the same type, which was assigned as wild type; 21 alleles revealed a nucleotide substitution resulting in silent mutation; and the remaining 12 alleles showed five types of nucleotide deletion or substitutions resulting in one frameshift and four missense mutations. Three of them, A74G, 812delT and L572V, were novel mutations. None of the study subjects showed homozygous frameshift or missense mutated alleles. We also studied the association between toxic response to 5FU and heterozygous frame shift or missense mutation of the DPYD gene among eight cancer patients who had received 5FU‐based chemotherapy. These patients did not show any adverse effects higher than grade 3, suggesting that heterozygotes are not associated with increased toxicity to 5FU. Our results indicate that a very small percentage, about 0.2%, of the Japanese population seems to carry homozygous mutations in DPYD gene, mutations which possibly indicate genetically increased toxicity of 5FU‐based chemotherapy.

Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene.

For nearly a decade since the mapping of the multiple endocrine neoplasia type 1 (MEN1) locus to 11q13 and the suggestion that it is a tumour suppressor gene, efforts have been made to identify the gene responsible for this familial cancer syndrome. Recently, we have identified the MEN1 gene by the positional cloning approach. This effort involved construction of a 2.8-Mb physical map (D11S480-D11S913) based primarily on a bacterial clone contig. Using these resources, 20 new polymorphic markers were isolated which helped to reduce the interval for candidate genes by haplotype analysis in families and by loss of heterozygosity (LOH) studies in approximately 200 tumours, utilizing laser-assisted microdissection to obtain tumour cells with minimal or no admixture by normal cells. The interval was narrowed by LOH to only 300 kb, and nearly 20 new transcripts that map to this region of 11q13 were isolated and characterized. One of the transcripts was found by dideoxyfingerprinting and cycle sequencing to harbour deleterious germline mutations in affected individuals from MEN-1 kindreds and therefore identified as the MEN1 gene. The type of germline mutations and the identification of mutations in sporadic tumours support the Knudson's two-hit model of tumorigenesis for MEN-1. Efforts are being made to identify the function of the MEN1 gene-encoded protein, menin, and to study its role in tumorigenesis.