Hereditary Susceptibility Research Articles

Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework

PurposeGene–disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework. MethodsForty-two gene–disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene–disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification. ResultsOf all gene–disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the National Institutes of Health Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence. ConclusionClinicians and laboratory diagnosticians should note that <60% of the genes on clinically available panels have Strong or Definitive evidence of association with hereditary colon cancer or polyposis, and >40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.

Genetics of gastric cancer: what do we know about the genetic risks?

An appreciable number of patients with gastric cancer have an underlying hereditary cancer susceptibility syndrome as the cause of their gastric cancer, particularly those with early onset gastric cancer or a family history of gastric or other cancers. Pathogenic germline variants in specific genes account for the known gastric cancer predisposition syndromes. Germline genetic testing can identify individuals and their family members who carry inherited pathogenic gene variants, and thus have increased risk of developing gastric or other cancers. Ideally, germline pathogenic variants can be identified in family members before the onset of disease, when early detection or prevention strategies can be implemented most effectively to decrease gastric cancer- related morbidity and mortality. This article reviews some of the currently known gastric cancer predisposition syndromes and their associated cancer risks. We also discuss current research and advances in the field of genetic gastric cancer susceptibility.

Abstract 4160: PZP as a new gene associated with increased breast cancer risk

Abstract Germline mutations in known breast cancer (BC) predisposing genes account for only 20 - 25% of hereditary breast cancer susceptibility. In this study, we anticipated that application of exome analysis to a series of genetically homogeneous Slavic BC patients will allow to identify novel recurrent BC predisposing mutations. 49 BRCA1/2-negative BC patients with evident clinical signs of the hereditary disease (family history and/or BC bilaterality and/or young onset) were subjected to Illumina-based whole exome sequencing. Two patients were found to carry a rare nonsense mutation in pregnancy zone protein (PZP) gene (p.Arg680*, rs145240281). This mutation was further analyzed in a case-control study involving 1046 high-risk BRCA1/2-negative BC cases, 1608 consecutive BC and 1082 middle-aged tumor-free women. Distribution of PZP p.Arg680* alleles was in agreement with its putative BC-predisposing role: 4/1046 (0.38%) and 9/1608 (0.56%) BC cases vs. 1/1082 (0.09%) controls, producing risk estimates in consecutive BC group equal to 6.08 (95% CI 0.770 to 48.096, P = 0.087]. 5/15 heterozygous for PZP p.Arg680* variant patients were diagnosed with multiple primary tumors (2 bilateral BCs, BC + colorectal cancer, bilateral BC + gastric cancer, BC + basal-cell like skin cancer). To the best of our knowledge, no reports associating gene PZP to cancer pathogenesis are available. In order to evaluate the functional effects of PZP p.Arg680*, we obtained two heterozygous mutant clones of CRISPR/Cas9-modified MCF7 cells containing 10-bp and 4-bp deletions adjacent to the desired targeted location. The real-time quantitative PCR confirmed significant down-regulation of PZP transcript in the clones carrying CRISPR/Cas9 induced deletions. Since this mutation results in a truncated protein, we also performed shRNA mediated knock-down of PZP. To study the effects of PZP mutation on cell proliferation and apoptosis, CRISPR/Cas9- and shRNA-modified clones were treated with tamoxifen and etoposide for 72 hours. The results have shown a significantly higher inhibitory concentration (IC50) for both drugs and higher clonogenic potential in CRISPR/Cas9-modified PZP clones compared to control MCF7 cells. Apoptosis induction was quantified using AnnexinV/PI staining; the reduced apoptosis in PZP-defective clones was documented. Taken together, obtained data argue that PZP may function as a tumor suppressor gene, and truncating variant p.Arg680* can represent a moderate-risk breast cancer susceptibility allele. This work has been supported by the Russian Science Foundation (grant 17-15-01384) and DST/INT/RUS/RSF/P-11 Citation Format: Ekaterina Sh Kuligina, Anna P. Sokolenko, Rohit Kumar, Ilya V. Bizin, Aglaya G. Iyevleva, Kirill Zagorodnev, Syed K. Hasan, Aleksandr A. Romanko, Ashok K. Varma, Evgeny N. Imyanitov. PZP as a new gene associated with increased breast cancer risk [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 4160.

Analysis of Heritability and Genetic Architecture of Pancreatic Cancer: A PanC4 Study.

Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.

Unselected germline screening in pancreatic adenocarcinoma yields high rates of pathogenic and likely pathogenic variants (PV) in hereditary cancer susceptibility genes.

1582 Background: Recent literature cites a germline mutation rate of 3.9-15.1% in patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) depending on breadth of genes tested, pre-selection of high-risk history and population substructure. True incidence of germline mutations in PDAC is unknown in unselected population. Methods: All patients (pts) diagnosed with PDAC in the province of British Columbia, Canada and referred to the Hereditary Cancer Program, were eligible to undergo 30 gene Color saliva kit testing under a research protocol, or clinical multigene testing if they met existing local criteria regardless of whether they signed on to the protocol. Any healthcare provider or patients themselves could refer. Results: 243 pts were referred between August 2016 and October 2018 but 25.1% (61) declined and 9.1% (22) died before testing. Of the 141 pts who consented to research protocol and completed germline testing, median age was 64 (46.1-81.0), 68.8% were European, 1.4% Ashkenazi Jewish heritage, 42% male, 61% non-smoker, 24.1% had personal history of a second cancer and 39% had metastatic disease. Baseline characteristics were similar between the PV positive and uninformative group. 20/25 PV were in known PDAC susceptibility genes with cascade screening implications (ATM (9), BRCA2 (4), BRCA2/ATM (1), CDKN2A (4), and MSH2 (2)). Excluding the 3 PV identified through carrier testing (1) and prior research identification (2), the rate of PV in unselected, unrelated PDAC cohort is 22/138 (15.9%). Utilizing previous NCCN criteria for BRCA1/BRCA2 testing or for familial pancreatic cancer did not appear to select for patients with higher risk of PV positive (12/65 (18.4%) PV positive rate versus 13/76 (17.1%) in those that didn’t meet criteria). Previous criteria would have missed 52% (13/25) PV in ATM (6), BRCA2/ATM (1), BRCA2 (2), MSH2 (2), NBN (1), CHEK2 (1). To date, a third of families with PV identified have accessed cascade testing in 38 relatives. Conclusions: Given the high incidence of 15.9% PV in hereditary cancer susceptibility genes, our data support recommendations for universal germline genetic testing of PDAC pts.

Confirmation of germline variants identified by tumor testing: A population-based study.

e13021 Background: Multi-gene panel tumour testing (TT) has been available in British Columbia since mid-2016 for metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), melanoma (MEL), low-grade glioma (LGG), and gastro-intestinal stromal tumours (GIST). TT can detect somatic driver mutations and potential pathogenic germline variants (pPGVs) associated with hereditary cancer susceptibility. We reviewed the frequency of pPGVs identified by TT and examined referral rates to the Hereditary Cancer Program (HCP) for confirmatory germline testing (GT) and therapeutic implications of PGV findings. Methods: All patients (pts) undergoing TT testing from October 1, 2016 to December 31, 2018 were identified. Diagnosis, age, gender, family history and treatment data were obtained. TT was performed by next-generation sequencing for all/selected regions of the following genes: AKT1, ALK, BRAF, BRCA1, BRCA2, CCND1, CCND3, CIC, EGFR, ERBB2, ERBB3, FUBP1, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, ROS1, SDHA, SDHB, SDHC, SDHD. Results: Among 2937 TTs, pPGVs were identified in 83 pts (2.8%) [Table 1]. 50 pts (57%) were referred to HCP, 41 had germline testing, and 14 PGV were confirmed. PGVs were most commonly identified in BRCA1/2 and SDHA and these findings did not influence oncologic treatments. Conclusions: TT detected pPGVs in 2.8% of unselected pts with metastatic cancers. Among 41 pts undergoing germline testing, 34% who would not have otherwise met testing criteria, had a confirmed PGV. Referral rates were low due to lack of patient and clinician awareness and poor health status. Although PGV findings did not directly impact treatment, TT identified 14 new families with hereditary cancer who can benefit from early detection and screening. Future directions include expansion of TT to include additional hereditary cancer susceptibility genes and development of digital tools for pts and clinicians. [Table: see text]

MON-126 Fulminant Type 1 Diabetes Caused by "Jumping"

Background: Fulminant type 1 diabetes mellitus (FT1DM) is characterized by rapid onset of disease and complete destruction of pancreatic β-cell function. It is associated with genetic susceptibility, viral infection, autoimmunity and pregnancy. In this report, the patient jumped from a 2-meter-high platform, which caused acute pancreatitis and then induced FT1DM. Clinical case: A 40-year-old male suffered from abdominal pain after jumping from a 2-meter-high platform on June 7, 2017, and the pain was relieved slightly after about half an hour. On June 8, abdominal pain was worsen with fever up to 38.5℃. He was treated with antibiotics in the local hospital. But abdominal pain gradually increased, and was relieved in prone position. He was hospitalized on June 10. Pancreatic CT showed pancreatic edema and obvious exudation. Amylase was 201U/L(15-115)and lipase normal. He was diagnosed as “acute pancreatitis” and treated with somatostatin, antibiotics, proton pump inhibitors and so on. Fasting blood glucose is 4.96mmol/L and body temperature is normal on June 11. On June 13, obvious thirst appeared. On June 14, laboratory examinations showed fasting blood glucose was 25.69mmol/L, HCO3- 13.24mmol/L, a white blood cell count of 20.22×109/L,neutrophil percentage 87.6%, amylase 872U/L, lipase 141U/L, and HbA1c was 5.69%. Insulin was given to reduce blood glucose. On June 16, fasting blood glucose was 16.49mmol/L. On June 26, somatostatin and proton pump inhibitors were stopped and abdominal pain disappeared. Hypoglycemic drugs were adjusted to insulin glargine and aspart. He was admitted to our hospital on July 1st. His height and weight were 170cm and 59.5kg, respectively (body mass index 20.95kg/m2). Serum glucose was very high (15.24mmol/L), while HbA1c was relatively low (6.8%). Fasting, normal postprandial 1h and 2h C-peptide levels were zero. Islet-related autoantibodies against GAD and ZnT8 were positive and others were negative. Pancreatic magnetic resonance imaging and MRCP were normal. IgG, IgG4, complement C3, C4, antinuclear antibody spectrum, vasculitis group, antibody to beta 2 glycoprotein, anticardiolipin antibodies, thyroid peroxidase antibody and thyroglobulin antibody were negative. He was discharged after blood glucose was controlled with insulin glargine and aspart. The patient had class II HLA gene showed DQB1*04:01-DRB1*04:05 haplotype. Conclusion: In the background of hereditary susceptibility, acute pancreatitis was induced by jumping off a 2-meter-high platform, and leaded to FT1DM. This is the first case of FT1DM caused by jumping down from a high place.

Association between polymorphisms in MicroRNA target sites of RAD51D genes and risk of hepatocellular carcinoma.

RAD51D (RAD51L3) is a member of the RAD51 gene family which plays important roles in maintaining genomic stability and preventing DNA damage. This study is aimed to investigate the associations between RAD51D polymorphisms and the hereditary susceptibility of hepatocellular carcinoma (HCC). In this study we conducted a hospital–based case‐control study including 805 cases (HCC patients) and 846 controls (nontumor patients) in Guangxi, China. A total of two Single–nucleotide polymorphisms (SNPs) rs12947947 and rs28363292 of RAD51D were selected and genotyped. Although we did not find two SNPs individually that had any significant main effect on risk of HCC, We found that the combined genotypes with 1‐2 risk genotypes were associated with significantly increased overall risk of HCC (OR = 1.462, 95% CI = 1.050‐2.036). According to the results of further stratification analysis, GT/GG genotype of rs28363292 increased HCC risk in zhuang people (OR = 3.913, 95% CI = 1.873‐8.175) and nonhepatitis B virus (HBV) infection population (OR = 1.774, 95% CI = 1.060‐2.969), the combined 1‐2 risk genotypes increased the risk of HCC in zhuang people (OR = 2.817, 95% CI = 1.532‐5.182) and non‐HBV infected population (OR = 1.567, 95% CI = 1.042‐2.358). Our results suggest that rs12947947 and rs28363292 polymorphisms may jointly contribute to the risk of HCC. Further large studies and functional studies are required to validate our findings.

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility.

There is still around 50% of the familial breast cancer (BC) caseswith an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility.

Genetic analysis of Japanese patients with Fanconi anemia: novel findings

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies, resulting from mutations in one of the 22 known FANC genes (from FANCA to FANCW). The proteins encoded by these genes participate in a deoxyribonucleic acid interstrand cross-link repair pathway, the so-called FA/BRCA pathway. The 22 FANC genes include hereditary breast and ovarian cancer susceptibility genes, such as BRCA1 or BRCA2. Patients with FA display a wide range of clinical phenotypes owing to the genetic heterogeneity of the disease; therefore, the molecular diagnosis is critical for the appropriate management of such patients. Recently, we successfully subtyped 97% of the 117 Japanese patients with FA and identified 215 mutant alleles through a comprehensive strategy. In this review, the characteristics of genetic subtyping and mutated FANC gene variants in Japanese patients with FA and the genotype-phenotype correlation in FA are summarized. In addition, the carrier frequency of pathogenic FANC genes and risk of cancer among the FANC gene mutation carriers in general Japanese population are discussed.

Cognitive dysfunction and negative symptoms in patients with schizophrenia and their first-degree relatives from simplex and multiplex families.

PurposeThis study aimed to investigate cognitive functioning, negative symptoms, and the relationships in schizophrenia (SP) pedigrees and to explore the effect of genetic loading on those endophenotypes.Patients and methodsForty-four patients with SP, 81 first-degree non-psychotic relatives of patients from simplex and multiplex families, 14 matched control probands, and 29 first-degree relatives of the patients from communities were assessed by the vocabulary subtest (VS) of Wechsler Adult Intelligence Scale, memory span subtests of the Multiple Memory Assessment Scale (MMAS), Wisconsin Card Sorting Test (WCST), Continuous Performance Test (CPT), and Negative Scale of Positive and Negative Syndrome Scale.ResultsCompared with controls, patients with SP and their relatives had worse performances in WCST and CPT, and more serious negative symptoms. Patients from multiple families performed poorly on most tests while patients from simplex families had impairments only on the parameters of CPT and WSCT as compared to control probands. Patients from multiple families differed significantly from the patients from simplex families in the digit span and word span of MMAS. After controlling for education, in comparison with relatives of control probands, relatives from multiple families showed impairments in VS, multiple domains of CPT, whereas relatives from simplex families had lower scores on the VS and more total cards and random errors in WSCT. The performances of most tests were linked to negative symptoms in patients with SP. For patients with SP, VS, correct numbers and categories in the WCST, and visual and acoustic errors in the CPT predicted 68.8% of the variability in negative symptoms.ConclusionOur findings support that cognitive deficits and negative symptoms may be markers of hereditary susceptibility of SP and aggravate as the degree of genetic load increases. There are certain relationships between cognitive deficits and negative symptoms in patients with SP.

Stem cell therapy for treatment of thromboangiitis obliterans (Buerger's disease).

Thromboangiitis obliterans, also known as Buerger's disease, is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small- and medium-sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Stem cell therapy is an option for patients with severe complications, such as ischemic ulcers or rest pain. To assess the effectiveness and safety of stem cell therapy in individuals with thromboangiitis obliterans (Buerger's disease). The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 October 2017. The review authors searched the European grey literature OpenGrey Database, screened reference lists of relevant studies and contacted study authors. Randomized controlled trials (RCTs) or quasi-RCTs of stem cell therapy in thromboangiitis obliterans (Buerger's disease). The review authors (DC, DM, FN) independently assessed the studies, extracted data and performed data analysis. We only included one RCT (18 participants with thromboangiitis obliterans) comparing the implantation of stem cell derived from bone marrow with placebo and standard wound dressing care in this review. We identified no studies that compared stem cell therapy (bone marrow source) versus stem cell therapy (umbilical cord source), stem cell therapy (any source) versus pharmacological treatment and stem cell therapy (any source) versus sympathectomy. Ulcer healing was assessed in the form of ulcer size. The mean ulcer area decreased more in the stem cell implantation group: from 5.04 cm2 (standard deviation (SD) 0.70) to 1.48 cm2 (SD 0.56) compared with the control group: mean ulcer size area decreased from 4.68 cm2 (SD 0.62) to 3.59 cm2 (SD 0.14); mean difference (MD) -2.11 cm2, 95% confidence interval (CI) -2.49 to -1.73; 1 study, 18 participants; very low-quality evidence. Pain-free walking distance showed more of an improvement in the stem cell implantation group: from mean of 38.33 meters (SD 17.68) to 284.44 meters (SD 212.12) compared with the control group: mean walking distance increased from 35.66 meters (SD 19.79) to 78.22 meters (SD 35.35); MD 206.22 meters, 95% CI 65.73 to 346.71; 1 study; 18 participants; very low-quality evidence.Outcomes such as rate of amputation, pain, amputation-free survival and adverse effects were not assessed.The quality of evidence was classified as very low, with only one study, small numbers of participants, high risk of bias in many domains and missing information regarding tobacco exposure status. Very low-quality evidence suggests there may be an effect of the use of bone marrow-derived stem cells in the healing of ulcers and improvement in the pain-free walking distance in patients with Buerger's disease. High-quality trials assessing the effectiveness of stem cell therapy for treatment of patients with thromboangiitis obliterans (Buerger's disease) are needed.

"A change in perspective": Exploring the experiences of adolescents with hereditary tumor predisposition.

Hereditary tumor predisposition syndromes (HTPSs) are being recognized more frequently in the etiology of pediatric cancer. Previous research indicates that disclosure of tumor susceptibility is a significant event in adolescents' lives. Insight into adolescents' adjustment to knowledge of their syndromes can guide healthcare delivery, particularly genetic counseling. This study explored the experiences of adolescents with hereditary tumor predisposition and their perceptions of living at risk. Seven adolescents, ages 14 to 17, representing six different childhood-onset HTPSs, were purposively sampled and interviewed using a study-specific semistructured interview guide. We explored the disclosure process, support systems, and the perceived benefits and harms of knowledge of hereditary tumor susceptibility. Interview transcripts were analyzed via interpretive description. Three major themes emerged from the data: (1) The benefits of knowledge outweigh the harms; (2) context surrounding genetic testing must be recognized; and (3) self-concept is influenced but not defined by tumor risk. We conclude that adolescents recognize the challenges associated with awareness of tumor predisposition but may also identify positive aspects in their experiences, reflecting a changed life perspective. Results of this exploratory study suggest strategies that can guide pretest and posttest genetic counseling of adolescents for HTPSs, facilitating the adaptive incorporation of genetic information into an adolescent's self-concept.

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

BackgroundBreast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.MethodsTo specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.ResultsWe identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).ConclusionsOur study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

Abstract A29: Investigation of RECQL variants in European and African American breast cancer cohorts

Abstract Although an average woman in the United States can have a 12.5% lifetime risk of developing breast cancer (BC), inherited genetic risk variants can greatly influence a woman’s overall lifetime risk. Genes that harbor BC risk variants are referred to as BC susceptibility genes. Unfortunately, mutations in known BC susceptibility genes only explain approximately 35% of hereditary BC cases, leaving a large portion, approximately 65%, genetically unexplained. With the introduction of next-generation sequencing, several attempts have been carried out to identify additional hereditary BC susceptibility genes using whole-exome sequencing. The majority of these studies were relatively unsuccessful; however, Cybulski et al. (2015) successfully associated two rare truncation variants in RECQL, p.K555delinsMYKLIHYSFR and p.R215*, in a Polish and French-Canadian cohort, respectively. Subsequently, two additional studies were carried out in northern and southern regions of China, which also confirmed that overtly deleterious coding mutations in RECQL are associated with familial BC. Herein, we investigated RECQL variants in BC-affected African Americans (AAs) and European Americans (EAs). To our knowledge, this study represents the first attempt to identify an association between RECQL variants and BC cases in the United States. We initially screened all RECQL coding exons using polymerase chain reaction and Sanger sequencing in 49 BC cases (19 AAs and 30 EAs) from Alabama. Primarily synonymous variants were detected in both ethnicities; thus, in order to further investigate the role of RECQL synonymous variants in BC risk, we analyzed RECQL in blood-derived exomes of 168 and 580 BC-affected AAs and EAs, respectively, from The Cancer Genome Atlas (TCGA) project using an in-house bioinformatics pipeline. A case-control analysis revealed that all rare synonymous variants detected in EA BC cases were associated with BC, and p.S64= was significantly associated in both ethnicities. Interestingly, only one truncation variant was detected (p.Y492*) in all 748 BC cases analyzed. Unlike previous findings, this preliminary analysis suggests that rare RECQL synonymous variants may also increase an individual’s lifetime risk of developing BC; further investigation is warranted. Citation Format: Madison R. Chandler, Sydney Bergstresser, Anna LW Huskey, Elizabeth Stallworth, Amber Davis, Holly Dean, Brandon Johnson, Nancy D. Merner. Investigation of RECQL variants in European and African American breast cancer cohorts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A29.

Abstract 1240: Comprehensive analysis of germline variants in Mexican patients with hereditary breast and ovarian cancer susceptibility

Abstract Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high-risk pathogenic alleles in BRCA1 and BRCA2 genes, but only for 25% of HBOC cases. This work aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 31 non-cancer patients with a severe family history of cancer, using massive parallel sequencing. We found 15% (45/300) patients with pathogenic variants in the group of cancer patients; 12% (35/300) harbored variants with unknown clinical significance (VUS) and 73% (220/300) were negative. The non-cancer group had a 32% (10/31) of patients with pathogenic variants, 3% (1/31) had VUS and 65% (20/31) were negative. Moreover, the most recurrent mutation was the Mexican founder deletion of exons 9-12 in BRCA1, found in 5 of 16 cancer patients with alterations in this gene. Private or rare VUS variants with potential impact at protein level were found in 22 genes, being CHEK2 the one with most VUS (6/39). Noteworthy, our results show for the first time in the Mexican population an equal contribution of pathogenic alleles in other susceptibility cancer genes (50%) as in BRCA1/2 (50%). This highlights the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to broader gene panels. Further studies need to be conducted to define the clinical impact of the pathogenic alleles and VUS identified. Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara E. Díaz-Velásquez, Rina Gitler, María P. Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Lizbeth García Esquivel, Gabriela Torres-Mejía, Michael Dean, Ivan Delgado-Enciso, Héctor Ochoa-Díaz-López, Fernando Rodriguez-León, Virginia Jan, Victor H. Hugo Garzón-Barrientos, Pablo Ruiz-Flores, Perla K. Espino-Silva, Jorge Haro-Santa Cruz, Héctor Martínez-Gregorio, Ernesto Rojas-Jiménez, Rosa M. Álvarez-Gómez, Luis A. Herrera, Isabelle Romieu, Luis I. Terrazas, Yolanda I. Chirino, Cecilia Frecha, Javier Oliver, Sandra Perdomo. Comprehensive analysis of germline variants in Mexican patients with hereditary breast and ovarian cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1240.

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population

Background & aimHereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. MethodsThis multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. ResultsSeven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). ConclusionFour out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.

Universal genetic screening for Chinese colorectal cancer patients with higher hereditary susceptibility.

e13620Background: The incidence and death rates of colorectal cancer (CRC) in China have increased dramatically in recent decades. It is estimated that there were almost 376,000 new diagnoses of CR...

Family history of cancer as surrogate predictor for immunotherapy with anti-PD1/PD-L1 agents: preliminary report of the FAMI-L1 study.

Tumors related to hereditary susceptibility seem to have an immunosensitive phenotype. We conducted a multicenter retrospective study, to investigate if family history of cancer, multiple neoplasms and early onset of cancer could be related to clinical outcomes of anti-PD-1/PD-L1 therapy. Activity and efficacy data of 211 advanced cancer patients (kidney, non-small-cell lung cancer, melanoma, urothelium, colorectal and HeN), treated at seven Italian centers with anti-PD-1/PD-L1 agents, were analyzed. In this preliminary report at multivariate analyses, positive family history of cancer showed a statistically significant relationship with a better objective response rate (p=0.0024), disease control rate (p=0.0161), median time to treatment failure (p=0.0203) and median overall survival (p=0.0221). Diagnosis of multiple neoplasms significantly correlates only to a better disease control rate, while interestingly non-early onset of cancer and sex (in favor of female patients) showed significant correlation with a better median overall survival (p=0.0268 and p=0.0272, respectively). This pilot study seems to individuate easily available patient's features as possible predictive surrogates of clinical benefit for anti-PD-1/PD-L1 treatments. These preliminary results need to be confirmed with a greater sample size, in prospective trials with immunotherapy.

Thyroid cancer in adolescents and young adults.

In adolescents and young adults, thyroid cancer accounts for 13% of all invasive neoplasms, being three times more frequent in females, but overdiagnosis and overtreatment are common. There are two therapeutic approaches, one radical and no longer preferred in all instances, and the other conservative. Permanent complications of surgery and metabolic irradiation can affect quality of life and carry an economic burden. The overall survival rate approaches 100% for patients with differentiated thyroid cancer regardless of the extent of treatment. Medullary thyroid carcinoma is a very different entity, occurring most frequently in the context of hereditary tumor susceptibility syndromes.