Germline Mutations In Cancer Predisposition Genes Research Articles

Cancer predisposition genes in Japanese children with rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer-predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Twenty patients participated in this study. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Six pathogenic variants were found in five patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of BUB1B, LIG4, and MEN1. Two of the five patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. While this is the first report of the germline genetic analysis of Japanese children with RMS with detailed clinical information, the frequency of the variant was almost equivalent to that of previous reports from western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.

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.

Germline Genetic Testing for Breast Cancer Risk: The Past, Present, and Future.

The field of germline genetic testing for breast cancer (BC) risk has evolved substantially in the last decade. The introduction of multigene panel testing (MGPT) led to an urgent need to understand the cancer risk associated with several genes included in the panels. Although the research on understanding the cancer risk associated with mutations in several genes continues, there is also a need to understand the modifying effects of race and ethnicity, family history, and BC pathology on the prevalence of germline mutations and associated BC risk. Furthermore, polygenic risk scores (PRSs) to predict BC risk in patients with or without germline mutations in cancer-predisposition genes are now available for clinical use, although data on the clinical utility of PRSs are lacking. In patients with advanced BC associated with BRCA1/2 mutation, olaparib and talazoparib are now approved for treatment. In addition, molecular profiling studies are being used to clarify the BC tumor biology in mutation carriers to identify potential therapeutic options. In this article, we discuss these advances in the field of germline genetic testing and highlight current limitations and implications for clinical care.

Abstract 3001: Germline mutations in cancer predisposition genes and risk for subsequent neoplasms among long-term survivors of childhood cancer in the St. Jude Lifetime Cohort

Abstract Childhood cancer survivors are at increased risk of subsequent neoplasms (SN), largely considered to be therapy-related. Studies of cancer predisposition genes (CPGs) and risk of SN among long-term survivors are lacking. We characterized germline mutations in CPGs in childhood cancer survivors to determine their contribution to SN risk. Whole genome (30x) and exome (100x) sequencing was performed for 2988 5+ year survivors of childhood cancer (1629 leukemia/lymphoma, 332 CNS, 1027 other solid tumors, 53% male, median follow-up 28 [range 6-55] years). Survivors underwent a comprehensive clinical assessment, treatment exposures were abstracted from medical records, and SN were validated by pathology reports. Germline mutations in 63 CPGs were classified using the American College of Medical Genetics and Genomics guidelines as previously described (Zhang et al. NEJM 2015). Logistic regression, adjusting for age, sex and race, was used to evaluate associations between mutation status, cancer therapy and the SN risk. 1062 SNs were diagnosed in 437 survivors, of whom 98 developed ≥2 histologically distinct SNs. Median age at SN and time to first SN was 38.2 (range 3.3-67.4) and 29.2 (0.9-48.4) years, respectively. Common SNs were basal cell carcinoma (542 in 153 survivors), meningioma (201 in 100), thyroid (64 in 64), and breast cancer (58 in 50). Cumulative incidence of SN at age 45 was 25.5% (95% CI: 22.9-27.9). 169 survivors (5.7%) had a pathogenic/likely pathogenic (P/LP) mutation in a CPG, consisting of 97 single nucleotide variations, 63 insertion/deletions and 9 copy number alterations (49% of mutations not in ClinVar). Frequently mutated genes were: RB1 (n=41), NF1 (n=22), BRCA2 (n=13), BRCA1 (n=12) and TP53 (n=10). Our data confirmed known associations between CPG mutations and specific primary diagnoses including RB1 mutations in 32 of 41 (78%) of bilateral and 7 of 57 (12%) of unilateral retinoblastoma survivors, 22 NF1 (20 of 332 CNS survivors), 4 SUFU (all in medulloblastoma survivors) and 5 WT1 mutations (all in Wilms’ tumor survivors). Analyses revealed novel associations between CPG mutations and SN risk. Among 1326 survivors not exposed to radiation therapy (non-RT), 62 SNs developed in 54 survivors, of which 15 (24.2%) occurred in P/LP mutation carriers. Non-RT exposed survivors with a P/LP mutation had an increased risk of SN (OR=5.6, 95% CI=2.6-12.0, P<0.001) and the odds of developing ≥2 distinct histologic types of SNs was increased by 23.6-fold (95% CI=5.4-102.7, P<0.001). In 1662 RT exposed survivors, P/LP-mutation carriers had an odds ratio of 2.3 (95% CI=0.9-6.0, P=0.08) for developing ≥2 distinct histologic types of SNs. Our findings indicate that a substantial proportion of non-RT exposed childhood cancer survivors who develop one or more SN carry a CPG mutation, and should be referred to genetic testing and counseling services. Citation Format: Zhaoming Wang, Carmen L. Wilson, John Easton, Dale Hedges, Qi Liu, Gang Wu, Michael Rusch, Michael Edmonson, Shawn Levy, Jennifer Q. Lanctot, Eric Caron, Kyla Shelton, Kelsey Currie, Matthew Lear, Heather L. Mulder, Donald Yergeau, Celeste Rosencrance, Bhavin Vadodaria, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Shuoguo Wang, Ti-Cheng Chang, Stephen Rice, Andrew Thrasher, Aman Patel, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Deo Kumar Srivastava, Chimene A. Kesserwan, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang. Germline mutations in cancer predisposition genes and risk for subsequent neoplasms among long-term survivors of childhood cancer in the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3001. doi:10.1158/1538-7445.AM2017-3001

Incidence of Germline Mutations in Cancer-Predisposition Genes in Children with Hematologic Malignancies: a Report from the Pediatric Cancer Genome Project

▪Pathologic germ line mutations that predispose patients to cancer are estimated to occur in 4-30% of all pediatric oncology cases. In addition to leukemia specific familial predisposition syndromes, children with rare constitutional syndromes, heterogeneous dysmorphic syndromes, and multiple-cancer hereditary predisposition syndromes are all at an increased risk for hematologic malignancies. However, to date no genome-wide analysis has been done to define the range of germ line mutations that occur in pediatric patients with hematological malignancies.To determine the frequency of pediatric cancer patients that have germ line variants of pathological significance in genes that predisposed to cancer, we analyzed the germ line and tumor DNA from 1120 pediatric cancer patients that were enrolled in the St. Jude – Washington University Pediatric Cancer Genome Project (PCGP). Samples were analyzed by whole-genome sequencing (n = 595), whole-exome sequencing (n = 456), or both (n = 69). Single nucleotide variants (SNVs), insertions/deletions (indels), structural variations (SV) and copy number alterations (CNAs) were detected using our analytical pipeline and all single nucleotide polymorphisms (SNPs) previously identified in non-cancer populations were filtered out. Our analysis then focused on the 23 cancer predisposition genes recently recommended for germ line analysis by the American College of Genetics and Genomics, along with an additional 8 genes that have been previously shown to predispose to pediatric cancer at a high penetrance. All variants in these 31 genes were classified as pathologic, likely pathologic, uncertain significance, likely benign, and benign based on literature review and in-silico predictions on the effect of novel mutations. An expanded analysis including a total of 565 genes known to play a role in oncogenesis was also evaluated.Pathologic or likely pathologic germ line variants in one of the 31 genes were detected in 8% (90/1120) of patients, including: 16% (46/287) of patients with solid tumors, 8.6% (21/245) with brain tumors, and 3.9% (23/588) with leukemia. Expanding this analysis to 565 cancer gene resulted in only a slight increase, with a pathologic or likely pathologic variant being detected in 8.6% (97/1120) of patients. The most frequently effected genes included TP53 (n=48), APC (n=7) and BRCA2(n=6). Importantly, in >50% of these patients, analysis of their tumor DNA revealed the absence of a wild type allele for the cancer predisposition gene that was altered in the germ line.The 588 pediatric patients with leukemia included 116 acute myeloid leukemias (AMLs: FAB M7 n=20; Core Binding Factor leukemias n=86; MLL-R n=10) and 472 acute lymphoblastic leukemias (ALLs: E2A-PBX1 n=53; ERG-R n=39; TEL-AML1 n=53; Hyperdiploid n=69; Hypodiploid n=47; BCR-ABL1 n=40; T-ALL n=32; MLL-R n=40; BCR-ABL-like n=31; and Other n=68). Across this cohort, 3.9% (23/588) of leukemia patients harbored a pathologic germ line mutations in one of the 31 cancer pre-disposing genes. This number increased to 4.6% (27/588; 28 mutations) when the expanded gene list was evaluated. TP53 (n=10) was the most frequently altered germ line gene in pediatric leukemia patients and was found predominantly in low-hypodiploid ALL, as previously reported. Germ line pathologic variants were also identified in KRAS, RUNX1, APC, BRCA2, and RET (2 cases each), and NRAS, SH2B3, BRCA1, MUTYH, PTCH1, SDHA,VHL, and NF2 (1 case each). Although germ line mutations in RUNX1 and SH2B3are typically associated with myeloid neoplasms, we identified these lesions in 3 cases of B lineage ALL suggesting an association with a wider spectrum of leukemia.In conclusion, a small but significant proportion of pediatric patients with leukemia carry a germ line variant of pathologic significance in a cancer predisposition gene. These results suggest that these germ line lesions likely play a direct role in the pathogenesis of the patient’s presenting leukemia. Moreover, our results suggest that these patients would benefit from future clinical surveillance for the development of a second cancer. Lastly, these data demonstrate the power of comprehensive next generation DNA/RNA sequencing for the identification of pediatric patients who carry a germ line pathologic variant in a cancer predisposition gene. DisclosuresNo relevant conflicts of interest to declare.