Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and ...the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes
, and
result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair-deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families.
Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome ...can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (
and Suppressor of fused (
mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in
mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in
or, more rarely,
, each of which encodes a chromatin remodeling family member.
mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of
and
mutations.
The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity.
From 1,730 French patients ...suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation.
The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations.
The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.
Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the
tumor suppressor gene encoding p53, a transcription factor triggered as a protective ...cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS.
Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October ...2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (
and
), juvenile polyposis coli (
and
), Peutz-Jeghers Syndrome (
/
), and PTEN hamartoma tumor syndrome (PHTS;
), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series.
.
hamartoma tumor syndrome (PHTS),
syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant ...neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years.
syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended.
Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress ...has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.
Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, ...with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.
Abstract Background The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. Objective To study consistency in phase-II clinical trials ...evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Methods Systematic review of clinical trials registered on clinicaltrials.gov , clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Results Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. Conclusion No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.
Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic ...option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
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