Genetic predisposition to cancer: surveillance and intervention Melissa Perrino , Jo Cooke-Barber , Roshni Dasgupta , James I. Geller PII: DOI: Reference:
S1055-8586(19)30116-7 https://doi.org/10.1016/j.sempedsurg.2019.150858 YSPSU 150858
To appear in:
Seminars in Pediatric Surgery
Please cite this article as: Melissa Perrino , Jo Cooke-Barber , Roshni Dasgupta , James I. Geller , Genetic predisposition to cancer: surveillance and intervention, Seminars in Pediatric Surgery (2019), doi: https://doi.org/10.1016/j.sempedsurg.2019.150858
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Genetic predisposition to cancer: surveillance and intervention Melissa Perrinoa, Jo Cooke-Barberb, Roshni Dasgupta b, James I. Gellera,*. a
Department of Pediatrics, Division of Oncology, Cincinnati Children‘s Hospital Medical Center,
University of Cincinnati b
Division of Pediatric General and Thoracic Surgery, Cincinnati Children‘s Hospital Medical Center,
University of Cincinnati
*Corresponding Author: James Geller, MD Division of Oncology 3333 Burnett Ave Cincinnati, OH 45229 Cincinnati Children‘s Hospital Medical Center Cancer and Blood Disease Institute [email protected]
Phone: 513-636-6312 . Word Count: Abstract: 138; Manuscript Text: 3746 Tables: 1; Figures: 0
Abstract Cancer is one of the leading causes of early mortality for children and adolescents. Identifiable genetic cancer predisposition conditions account for a growing proportion of pediatric and adolescent cancer, likely due to increasing knowledge about various predisposition conditions, more widespread cancer genetic counseling, and available diagnostics. Greater awareness, data-driven surgical intervention and clinical surveillance can help facilitate cancer prevention and early detection at cancer stages more amenable to cure. An extensive literature review of published studies and expert opinion with consensus guidelines are reviewed. Specific syndromes where genetics, imaging and surgical intervention are utilized to benefit affected patients and families are presented. In many tumor predisposition syndromes, the underlying genetic diagnosis is made concurrently, or after, malignancy is identified. Improved recognition of underlying predispositions, along with appropriate surgical interventions and imaging surveillance should lead to increased patient survival.
Introduction: The revolution of next generation sequencing (NGS) and analysis of cancer genetics has brought a wave of personalized medicine for many patients. For patients with cancer predisposition syndromes, increased awareness, counseling, diagnostics and ultimate surveillance recommendations are emerging, facilitating earlier cancer detection and treatment. Cancer predisposition syndromes, previously described based on clinical observation alone, have recently undergone rapid refinement in characterization along with expansion of our appreciation of clinical and genomic heterogeneity. The ability to quantify patient-specific risks of malignancy, while often still poorly understood, has improved, as focus on phenotype-genotype correlation has advanced. Understanding cancer predisposition syndromes, supported by appropriate imaging and surgical intervention, can increasingly be utilized to benefit identify and treatment of affected patients. In 2017, The American Association for Cancer Research (AACR) annual meeting included a Childhood Cancer Predisposition Workshop. As a result, a series of manuscripts, with the goal to provide recommendations for screening surveillance in specific predisposition syndromes, has been published1-11. An overall review of cancer genetic predisposition syndromes is provided herein. The evolution of surveillance recommendations for specific cancer predisposition syndromes, presented in themes of genetic etiology, are highlighted, focusing on the potential impact of surgical intervention and overall patient care. The nuanced field of genetic, ethical, and psychosocial care for affected patients and families with cancer predispositions are the subject of other reviews and not included herein.12-14 A summary of various cancer predisposition syndromes, presented in groups (single gene mutation, overgrowth, Rasopathies, polyposis, neuroendocrine, other-embryonal, PTEN/PI3k/AKT pathway, and DNA repair defects) are described in Table 1. Examples from the various subgroups, focusing on common, representative and/or syndromes for which surveillance and surgical intervention are possible, are highlighted below.
Single gene mutation cancer predisposition syndromes not otherwise sub-grouped: Several cancer predisposition syndromes characterized by underlying single gene mutations not otherwise defined in a sub-group include Li Fraumeni Syndrome (LFS) and Hereditary Retinoblastoma (HRB). LFS, an autosomal dominant syndrome due to a germline mutation in p53, presents with a near 100% lifetime risk of malignancy. Patient‘s generally present with representative cancers earlier than otherwise predicted in non-LFS patients, typically before 45 years of age. The more common LFS-associated pediatric cancers include choroid plexus carcinoma, high grade glioma, sarcoma, Wilms tumor, leukemia and adrenocortical carcinoma.15 A pilot screening study for identified LFS patients demonstrated a survival advantage for those LFS patients electing to undergo scheduled surveillance.16 Specifically, identification of tumors at early stages and before symptoms developed correlated with improved overall survival. False positives resulting in possibly unnecessary surgical intervention occurred in just 2 of 59 patients. These patients presented with persistent musculoskeletal hyperintensity due to a bone cyst and benign inflammatory changes. Neither patient experienced a complication from surgical intervention. Longer term follow up of this cohort study demonstrated remarkably minimal false negatives as well as strong compliance with the proposed screening protocol.17 This ‘Toronto screening protocol‘ includes yearly whole body MRI, brain MRI, every 6 month abdominal/pelvic ultrasound, yearly dermatologic exams and every 3-4 month urinalysis and lab monitoring (complete blood count, lactate dehydrogenase, erythrocyte sedimentation rate, β-human chorionic gonadotropin, alpha-fetoprotein, 17-OH-progesterone, testosterone, dehydroepiandrosterone sulfate, and androstenedione). Hereditary retinoblastoma (HRB) is an autosomal dominant syndrome due to germline loss of RB1, a tumor suppressor gene. Dr. Alfred Knudson first described the ―two hit hypothesis‖ in Hereditary Retinoblastoma in 1971.18 Greater than 1,000 distinct RB1 mutations have been identified, with preliminary insights on phenotype/genotype, including low penetrant and high penetrant
mutations.19 Additionally, the contiguous loss of part of chromosome 13q (13q deletion syndrome) often includes the RB1 gene, presenting with HRB and additional clinical manifestations (dysmorphic features, developmental delay).20 Patients with HRB are at increased risk of retinoblastoma (approaching 100% in null mutations, often bilateral disease) and osteosarcoma or other soft tissue sarcomas. Sarcomas often present as a second malignancy in areas of previous radiation, but not exclusively. Patients are also at risk for brain tumors (pineal or hypothalamic tumors); that is, ‗trilateral‘ retinoblastoma. Surveillance by an ophthalmologic oncologist and pediatric oncologist (with brain MRI surveillance) are indicated to enhance early detection and therapy, as indicated. Such surveillance is most intense during the first 5 years of life, the period of highest risk for RB and brain tumors, after which yearly clinical assessments may be sufficient.1 Rasopathies Syndromes characterized by genetic perturbation of the RAS/MAPK pathway are often referred to as ‗rasopathies‘. The rasopathy Neurofibromatosis Type I (NF1) is the most common monogenic inherited disease, occurring in 1:3,000 live births. NF1 occurs with heterozygous germline loss of Neurofibromin, a gap-domain tumor suppressor gene. Loss of Neurofibromin results in overexpression of the RAS/MEK/ERK pathway.21 Patients with NF1 have increased risk of developing optic pathway and other gliomas, malignant peripheral nerve sheath tumors (MPNST), as well as other soft tissue sarcomas, and leukemia, specifically juvenile myelomonocytic leukemia (JMML).22 While controversial, radiologic screening for optic pathway gliomas has been proposed, with the potential for decreasing visual field defects.23 Current consensus guidelines propose visual field exams every 6 months until 8 years old, with close radiologic follow up if abnormalities are discovered.2 While MPNSTs are rare, they are often diagnosed in late stages and remain the leading cause of early mortality for NF1 patients. Complete surgical resection is the only potential curative option, and is often not feasible due to location of tumor and invasion of vital structures. While technically benign, plexiform neurofibromas can lead to substantial morbidity, and occasional mortality, presenting as a challenge to a multidisciplinary team including pediatric oncology, radiology
and surgery. Routine screening for MPNST is not currently recommended; however close attention to change in neurofibroma growth, neurologic function or pain warrants prompt assessment. Baseline whole-body MRI has been proposed in adolescents (16-20 years old) to identify overall tumor burden, useful for future comparison.2 FDG-PET scanning can be useful to guide biopsy for identifying potential MPNST components within or evolving from neurofibromas.2 Leigus Syndrome, a rasopathy associated with SPRED1 mutations, predisposes affected patients to desmoid tumors and breast cancer. Noonan syndrome, predominantly due to mutations in PTPN11, is characterized by predisposition to JMML and myelodysplastic syndrome (MDS), Hodgkin and non-Hodgkin lymphoma, neuroblastoma and dysembryoplastic neuroepithelial tumors.24 For the above syndromes, the true cancer risk is not well established and screening recommendations have not been validated.3 Patients are encouraged to seek early medical care for new symptoms; physicians need to have a thorough understanding of malignancy risk to guide diagnostics. Overgrowth Syndromes Cancer predisposition syndromes characterized by anatomic overgrowth have a commonality of predisposition to Wilms tumor and Hepatoblastoma, with more specific risks narrowed by individual diagnosis. Many of the common overgrowth conditions, such as Beckwith Wiedemann Syndrome and Perlman Syndrome, ultimately result in embryonal visceral tumors presumably through elevated levels of IGF2, either directly by impacting IGF2 expression via genomic perturbation at 11p15, or indirectly.25 Beckwith Wiedemann Syndrome (BWS), the most common overgrowth syndrome associated with malignancy risk, is due to a variety of complex genetic inheritance patterns, each with different cancer predisposition penetrance.4,26 Two clusters of imprinting control regions (IC1 and IC2) have altered expression, located at 11p15. IC1 is methylated by the paternal allele and is telomeric; IC2 is methylated by the maternal allele and is centromeric. Further, the IC2 cluster contains CDKN1C
(maternally expressed) and KCNQ1OT1 (LTI1, paternally expressed). Patients can also have mosaic paternal uniparental disomy (pUPD) of 11p15. The risk of malignancy in BWS due to IC1 hypermethylation and pUPD are 28% and 16%, respectively, whereas malignancy risk in BWS due to hypomethylation of IC2 and CDKN1C loss of function mutations are 2.6% and 6.9%, respectively. Wilms tumor is rarely associated with the CDKN1C and IC2 subgroups, but the IC1 subgroup carries a 21.1% increase in Wilms tumor risk. Hepatoblastoma and adrenal carcinoma are more common in patients with pUPD, whereas neuroblastoma is seen more frequently in patients with CDKN1C mutations. With the above differences in malignancy risk, screening can be tailored to specific molecular abnormality. Maas et al. proposed no screening for IC2 hypomethylation patients whereas pUPD patients should have an abdominal ultrasound (abd US) every 3 months until 4 years of age for Hepatoblastoma, and 5 years of age for Wilms tumor. Patients with IC1 hypermethylation should receive Wilms tumor screening (abd US every three months until 5yo) but do not need Hepatoblastoma screening. CDKN1C mutations carry recommendations for Wilms tumor, Hepatoblastoma, and additionally neuroblastoma urine studies and imaging.27 Some authors suggest screening patients with overgrowth syndromes for Wilms tumor through age 7 years.28 By knowing the specific molecular abnormality, clinicians and families can better discuss screening recommendations and follow up. Sotos syndrome is another characteristic overgrowth syndrome, with de novo mutations in NSD1. Sotos syndrome patients have excessive birth length, advanced bone age, and high incidence of seizures. Patients with Sotos syndrome have been described with neuroblastoma, leukemia, teratomas and hepatoblastoma, but their risk is estimated at <5%, questioning the utility of screening.4 Bohring-Opitz syndrome (ASXL1 mutations) and Simpson-Golabi-Behmel syndrome (GPC3/GPC4 mutations) can also be associated with Medulloblastoma. Mulibrey nanism is a rare syndrome due to TRIM37 mutations, with known risk for pheochromocytoma and GU malignancies including Wilms. Screening guidelines for these conditions have been proposed, but remain debated (Table 1).
Polyposis Syndromes Common polyposis syndromes include Familial Adenomatous Polyposis (FAP), MUTHY-associated polyposis, Peutz Jehgers Syndrome and Juvenile Polyposis syndrome.5 Familial Adenomatous Polyposis (FAP) is an autosomal dominant syndrome associated with mutations in the adenomatous polyposis coli (APC) gene. FAP is characterized by >100 gastrointestinal adenomas, but should be considered in patients who develop more than 20 lifetime adenomas, or extracolonic manifestations known to be associated such as a desmoid tumor and/or hepatoblastoma. Colon cancer risk seems proportional to adenoma burden, with a lifetime risk approaching 100% by 40 yo without a prophylactic surgical colectomy.29 Desmoid tumors and duodenal cancer account for the majority of deaths related to FAP. Mutations at codons 1061 and 1309 have increased risk of malignancy, with higher numbers of polyps at earlier ages, compared to mutations at the 3‘ site through codon 1399, 30 who have a predilection to develop desmoid tumors, often precipitated by abdominal surgery (prophylactic proctocolectomy). Discussions between treatment teams and patients need to include preventative surgical intervention, use of minimally invasive techniques that may mitigate desmoid formation, vs continued close surveillance with specific disease mutations. For FAP patients, diagnosed either with gene confirmation or clinically in the appropriate clinical/familial setting, a surveillance flexible sigmoidoscopy should be performed at 10 yo with biopsy of any polyps. If there is no evidence of polyp formation, flexible sigmoidoscopy can be performed every 2 years until polyps are detected prompting colonoscopy, or until age 16 at which time colonoscopy should be performed every 2 years until 20 yo. If adenomas have not been detected by age 20 it is reasonable to gradually extend surveillance colonoscopy until polyps develop. When polyps are discovered on flexible sigmoidoscopy, a formal colonoscopy should be performed to document complete examination of the colon. Patients should also be screened for duodenal adenomas with an esophagogastroduodenoscopy between age 20-25 and repeat examinations and
interval follow up EGD should be determined based on the Spiegelman stage which characterizes duodenal adenomas. Annual thyroid ultrasound should be considered to screen for thyroid cancer, however, there is no consensus regarding what age thyroid screenings should begin. 31 Some advocate for Hepatoblastoma screening when FAP is diagnosed at an early age; however, with a risk of only 2%, such screening has not been standardized. Surgical therapy for patients with FAP is aimed at mitigating the risk of developing gastrointestinal tract malignancy. The two main considerations for FAP patients are timing of surgery and type of surgery. If no malignancy is detected on surveillance colonoscopy, it is generally accepted practice to postpone prophylactic proctocolectomy until the child reaches young adulthood. This approach can be helpful by allowing emotional and psychosocial development of the child to take place prior to undergoing surgery. Reliability of follow up is also an important consideration with respect to surgical timing. There are historically four accepted surgical options: 1.) total colectomy with ileorectal anastomosis (IRA), 2.) total proctocolectomy with creation of ileal pouch and ileo-anal anastomosis (IPAA), 3.) total proctocolectomy with mucosectomy, creation of ileal pouch, and handsewn anal anastomosis, and 4.) total proctocolectomy with end ileostomy. Each surgical option has its own benefits and quality of life considerations. There is an inherent risk of malignancy associated with total colectomy with ileorectal anastomosis, especially if there is a large burden of rectal polyps, high grade dysplasia present, adenomas that are larger than 30 mm, or a severe phenotype (greater than 1000 adenomas). For the patients that undergo rectal sparing procedure, ongoing surveillance and reliability to follow up is necessary. A meta-analysis of 12 studies with a total of 1002 patients comparing the rectal sparing IRA procedure versus IPAA, measuring quality of life outcomes including bowel movement frequency and incontinence, demonstrated there are significantly less frequent bowel movements and less incontinence with the rectal sparing IRA procedure.32 The IPAA procedure is known to have a very low rate of malignancy with only 24 case reports reported in the literature.31 Total proctocolectomy with mucosectomy carry a 22% risk of malignancy in the remnant rectal mucosa at 10 years.31
Neuroendocrine Tumor Predisposition Syndromes Von Hippel Lindau (VHL) is an autosomal dominant mutation that predisposes patients to hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, and pancreatic neuroendothelial tumor (PNET). VHL is inherited as an autosomal dominant syndrome due to mutations in the VHL gene. Over 300 unique VHL mutations have been identified including gene deletion, missense and frameshift mutations. Patients with VHL have both increased risk for malignancy, as well as increased risk of benign growths. Therefore, screening with a careful attention to risk factors for malignancy is needed to address potential false positive and false negative imaging findings.33 Current screening recommendations include yearly eye exams, audiograms every 2 years (starting at 5yo), MRI brain and spine every 2 years (starting at 8yo), MRI abdomen yearly (starting at 10 yo). Urine studies every year to assess for pheochromocytoma should start at 2 yo.6 Abnormalities identified on imaging needs to be monitored closely, and intervention based on characteristic (hormone/symptom producing; for example) and size of lesions (<3cm renal and pancreatic tail and body, <2cm pancreatic head) can decrease risk of metastasis and improve organ function by allowing partial resection.34 Phenotype-genotype correlations are evolving for VHL; for example missense mutations are predominantly associated with the development of pheochromocytoma.34 At this time, there is no change to surveillance based on specific genetic mutation. Hereditary paraganglioma and PHEO syndromes (HPPS) are genetic predisposition syndromes that also have high incidence of both benign and malignant tumors. Neuroendocrine malignancies are the most common. Benign tumors typically involve tissue of neural crest origin. Molecular features of HPPS include aberrations in the succinate dehydrogenase enzyme complex (SDHx) and non-SDH genes MAX, TMEM127, HIF2a, ENGLN1 and KIF1β. Genotype-phenotype correlations are still being uncovered for HPPS, although higher risk for malignancy has been linked to SDHB deficiency.6
Multiple Endocrine Neoplasia (MEN) syndromes and Hyperparathyroid-Jaw tumors syndrome (HPT-JT) also predispose to neuroendocrine malignancies, with defined screening algorithms recommended.7,35 MEN1 is associated with variants in MEN1 (11q13), whereas MEN2A and 2B are associated with mutations in the RET proto-oncogene, and MEN4 is associated with CDKN1B germline mutations. HPT-JT is due to truncating mutations (occasional missense mutations) in CDC73. Overall, the above syndromes are characterized by both benign and malignant tumors of neuroendocrine origin, and screening recommendations are listed in Table 1.6,7 Patient‘s known to have MEN-2A syndrome should undergo prophylactic thyroidectomy between age 5 to 8 and it is generally accepted practice that these patients do not require prophylactic central node dissection.36 MEN-2B is typically aggressive and presents in infancy, much sooner than MEN-2A. These patients should be considered for early prophylactic thyroidectomy before 1 yo if a diagnosis of MEN-2B has been made. 50% of patients with MEN-2B will also develop pheochromocytoma which is an important surgical consideration, as pheochromocytoma; warranting screening, will need to be identified and resected prior to prophylactic thyroidectomy.37 Other Embryonal Cancer Predisposition Syndromes This classification of genetic syndromes is characterized specifically by the histopathology and embryological origin of tumors occurring in affected patients. Greater than 50 known genetic conditions have been reported to be associated with Wilms tumor, and is beyond the scope of this review.4, 38 When such conditions are suspected, whether presenting as unilateral or bilateral Wilms tumor, consideration for pre-operative chemotherapy to enhance potential nephron sparing surgery is regarded by some as standard practice.39 Guidelines for partial nephrectomy in Wilms predisposition syndromes are evolving. Pleuropulmonary Blastoma (PPB), the most common primary lung cancer in children, is most often due to constitutional mutations in DICER1, a gene involved in microRNA processing. PPB, lung cysts, and thyroid cysts/goiters are the most common abnormalities found in patients with loss of
function DICER1 germline mutations. PPB, follicular thyroid carcinoma, renal sarcoma, Wilms tumor, pineoblastoma, sertoli-leydig cell tumor, intraocular medulloepithelioma, hepatic mesenchymal hamartoma and other GU embryonal tumors are now well recognized tumors associated with germline DICER1 mutations.8 Screening is increasingly emphasized for these patients as we learn early surgical intervention for low-grade, and small size cysts improves OS and has decreased morbidity, especially for pulmonary or renal function.40 Screening recommendations are lifelong and frequent, with chest XR and abd US recommended every 6mo from birth-8yo, then yearly 8yo-12yo. Chest CT is advised once at 3-6mo and again at 3yo if initially normal. Thyroid ultrasounds are recommended every 3 years starting at 8yo; and pelvic/abdominal US is recommended for females starting at 8yo and continuing every 6 mo until 40yo.8 PTEN/PI3K/AKT Pathway PTEN hamartoma tumor syndromes (PHTS) combines distinct syndromes previously described and classifies them as one based on germline mutation of PTEN.41 Cowden syndrome, Bannayan–Riley– Ruvalcaba syndrome (BRRS), adult Lhermitte–Duclos disease have all been grouped into PHTS, although the majority of these patients present with Cowden syndrome. BRRS has significant overlap with Cowden syndrome, but occurs much earlier in life. Associated cancers most commonly include gastrointestinal, breast, thyroid and endometrial. Morbidity from benign growths is also substantial, with hamartomas occurring nearly anywhere. The National Comprehensive Cancer Network (NCCN) has developed diagnostic guidelines and proposed screening recommendations for PHTS.42 While not limited to embryonal tumors and overlapping with overgrowth syndromes, additional germline perturbations of the PI3kinase/AKT/mTOR/PTEN pathways have been identified. Proteus syndrome and PIK3CA-related overgrowth spectrum (PROS), the latter including CLOVES syndrome and Klippel-Trenaunay Syndrome (capillary venous lymphatic malformation with overgrowth) are due to perturbed PI3K/AKT gene signaling pathway. Proteus syndrome is caused by activating AKT1 mutation and PROS is caused by variants in PIK3CA.43,44 It has been suggested that patients with
PROS undergo renal ultrasounds every 3 months through age 7 years, with highest risk for Wilms tumor in the first 3 years.43 The tumor predisposition risks for patients with Tuberous sclerosis, due to mutations of TSC1 and TSC2, include sub-ependymal giant cell tumors (SEGA) of the central nervous system, and angiomyolipoma and renal cell carcinoma of the kidneys. 45 DNA repair deficiencies: Constitutional mismatch repair deficiency (CMMRD), a condition presenting with aggressive cancer early in life (colorectal carcinoma, brain tumors and leukemia/lymphoma), is a genetic predisposition syndrome characterized by biallelic loss of mismatch repair (MMR) genes. CMMRD has only recently been recognized as an individual disease entity with increased genetic testing. CMMRD occurs when a patient has bi-allelic mutations in the same genes causative of Lynch Syndrome (LS), which harbors monoallelic mutations (hMLH1, hMSH2, MSH6, PMS1, PMS2). Similar to NF1, CMMRD patients may present with cutaneous findings.46 The currently proposed screening for CMMRD patients includes Brain MRI every 6 months to monitor for brain tumors, whole body MRI (WBMRI) yearly for soft tissue sarcomas and other malignancy starting at 6yo, abdominal ultrasounds and bloodwork (complete blood count, lactate dehydrogenase, erythrocyte sedimentation rate) every 6 months evaluates for lymphoma and leukemia and can be alternated with WBMRI, and a yearly upper and lower endoscopy starting as early as 6 yo evaluates for polyp burden.9 DNA mismatch repair disorders like CMMRD primarily affects replication and does not portent increased toxicity sensitivity to chemotherapy and radiotherapy which is seen in the below DNA repair and telomere instability syndromes. Conversely, CMMRD tumors have demonstrated resistance to conventional chemotherapy, as some chemotherapeutic agents require intact mismatch repair to be effective, though early data supports potential cancer sensitivity to PD1 inhibitor based immunotherapies in CMMRD patients.9,47 Differentiating the underlying mechanism is important in guiding treatment decisions with families.
Fanconi anemia, Dyskeratosis Congenita, Ataxia Telangiectasia, and Bloom Syndrome are all clinical DNA breakage disorders due to deficiency in response to DNA damage. Patients with DNA breakage disorders have increased primary cancer risk as well as secondary cancer risk (from DNA toxins such as radiation and chemotherapy). Fanconi Anemia can result from a multitude of mutations (primarily the FANCx family) and results in cross-link repair difficulties. These patients are at increased risk of MDS and AML as well as squamous cell carcinomas. They are increasingly susceptible to standard chemotherapy/radiation treatments. Dyskeratosis Congenita results from abnormal telomere biology and has similar predisposition and risks as Fanconi Anemia.10 Surveillance imaging and treatments should account for these risks. Therefore, MRI and ultrasound imaging have emerged as the recommended imaging modalities. Syndromes such as Fanconi Anemia and Dyskaratosis Congenita are increasingly being treated with hematopoietic stem cell transplantation to prevent hematologic malignancies, with reduced intensity condition regimens in effort to limit risk of increased toxicity as well as secondary cancers.48 Ataxia Telangiectasia, due to biallelic mutations in ATM, is also characterized by the accumulation of DNA strand breaks leading to cell death and disease, and are particularly sensitive to radiation. No consensus surveillance recommendations for AT patients exist, but prompt clinical attention should be sought for new changes. Bloom syndrome, an autosomal recessive disorder due to biallelic mutations in BLM, results in DNA helicase deficiency and resultant accumulation of genomic instability. Malignancy is common and includes risk for leukemia and lymphoma, sarcomas, Wilm‘s tumor, meduloblastoma, and gastrointestinal cancers. Screening is highlighted by abdominal US for Wilms tumor until 8 yo, MRI for any new symptoms, and limiting ionizing radiation.48 Conclusion: Overall, cancer predisposition syndromes require increased clinical suspicion for initial diagnosis, and routine medical care throughout patients‘ lives. Prompt medical assessment, thoughtful imaging, and surgical interventions aimed at disease prevention and mitigation are part of the care team approach to improving outcomes. As genetic heterogeneity between syndromes evolves, so may risk for
individual patients. Close communication with a multidisciplinary team aware of the risks within specific predisposition syndromes will be required for the betterment of these patients.
Table 1. Syndrome Li Fraumeni
Mutation P53 CHEK2
NF type I
Beckwith Wiedemann Bohring–Opitz
DIS3L2 GPC3 or GPC4 APC
Familial paraganglioma/ Pheochromocytoma Multiple Endocrine Neoplasia 1
Multiple Endocrine Neoplasia 2A/2B HyperparathyroidJaw Tumor
CNS: Pituitary adenoma, Ependymoma, Meningioma Head/Neck: Parathyroid Adenoma Abd: Pancreatic Neuroendocrine tumor, Adrenal adenoma, Insulinoma Head/Neck: Medullary Thyroid ca Abd: Pheochromocytoma Head/Neck: Parathyroid ca, Jaw ossifying fibroma Abd: Wilms; GU: Ovarian carcinoma
5, 27-28 50
Juvenille Polyposis Von Hippel Lindau
Perlman Simpson–Golabi– Behmel Familial Adenomatous Polyposis MUTYH- polyposis Peutz Jehgers
lfsassociation.org Toronto Protocol
SPRED1 PTPN11, SOS1
Hereditary Retinoblastoma NF type II
Location: Tumors CNS: Medulloblastoma, Glioma, Choroid plexus ca Thoracic: Breast ca; Abd: Wilms, Adrenal ca MSK: Osteosarcoma, Soft tissue sarcomas Hematologic: Leukemia Skin: Melanoma Ocular: Retinoblastoma MSK: Sarcoma CNS: Schwannomas, Meningioma, Ependymoma Ocular: Retinal hamartoma CNS: Gliomas Abd: Gastrointestinal stromal tumor Skin: Dermal Neurofibroma MSK: MPNST, Rhabdomyosarcoma Hematopoietic: JMML Lipoma, Desmoid, Breast ca. CNS: Dysembryoplastic neuroepithelial Abd: Neuroblastoma Hematopoietic: JMML, Leukemia Abdominal: Neuroblastoma, Bladder ca Extremity: Rhabdomyosarcoma Abd: Hepatoblastoma, Wilms, Neuroblastoma, CDNK1C: Adrenal ca CNS: Medulloblastoma Abd: Wilms Head/ Neck: Thyroid ca Abd: Wilms, Renal Papillary ca, Pheochromocytoma GU: Ovarian ca, Endometrial adenocarcinoma Hematologic: ALL Abd: Wilms CNS: Medulloblastoma Abd: Wilms, Neuroblastoma, Hepatoblastoma CNS: Medulloblastoma Head/Neck: Papillary thyroid ca Abd: Hepatoblastoma, Intestinal ca, Desmoid Abd: Colon ca Thoracic: Breast, Lung Ca Abd: Colon and Pancreatic adenoca GU: Ovarian ca, Sertoli cell tumor Abd: Colon Ca CNS: Hemangioblastomas, Endolymphatic sac Abd: Renal Clear Cell ca, Pheochromocytoma, Neuroendocrine tumors CNS/paraspinal: Paraganglioma Abd: Pheochromocytoma, Gastrointestinal stromal tumor
PROS Proteus Syndrome
Hereditary pleuropulmonary blastoma
DKC1 (x- linked); many AD and AR
CNS: Medulloblastoma MSK: Rhabdomyosarcoma Hematologic: Lymphoma Head/Neck: Squamous cell ca Abd: Gastric ca, Anorectal squamous cell ca Hematologic: Myelodysplasia, leukemia
42 43 44 45
Telomere instabilit y
DNA base excision repair
PTEN hamartoma Tumor Syndrome
WT1, PAX6 WT 1, exon 8, 9 WT 1 intron 9 PTCH1, SUFU
WAGD Denys–Drash Frasier Gorlin
CNS: Atypical teratoid rhabdoid tumor, Schwannoma, Meningioma Abd: Malignant rhabdoid tumor; GU: SCCOHT (24yo) Abd: Wilms Abd: Wilms; GU: Gonadoblastoma, Juvenile granulosa cell GU: Gonadoblastoma, Dysgerminoma CNS: Medulloblastoma MSK: Rhabdomyosarcoma, Basal cell ca Thoracic: Breast ca, Thyroid, ca Abd: Renal cancer, Colorectal ca GU: Endometrial Skin: Melanoma Abd: Wilms Head/Neck: Parotid adenoma GU: ovarian cystadenoma CNS: supependymal giant cell astrocytoma Abd: angiomyolipoma, renal cell ca CNS: Pineoblastoma; Ocular: Meduloepithelioma Head/Neck: Thyroid, Nasal chondromesencymal hamartoma Thoracic: Pleuropulmonary blastoma Abd: Cystic nephroma, Renal sarcoma, Wilms, Mesenchymal Hamartoma; GU: Sertoli-Leydig cell tumor MSK: Rhabdomyosarcoma Head/Neck: Squamous cell ca Thoracic: Breast ca Abd: Hepatocellular ca, Wilms, Neuroblastoma GU: Vulvar, Cervical ca Hematologic: Myelodysplasia/Leukemia Hematologic: Leukemia, Lymphoma
DNA mismatch repair
Head/Neck: Oropharyngeal ca Thoracic: Breast ca; Abd: Wilms, Colon Ca bloomssyndrome MSK: Osteosarcoma association.org Hematologic: Leukemia, Lymphoma Skin: Melanoma Rothmund– RecQL4 MSK: Osteosarcoma Thompson Skin: Carcinomas Werner syndrome WRN CNS: Meningioma; Head/ Neck: Thyroid ca 10 MSK: Osteosarcoma, Fibrosarcoma, Leiomyosarcoma, Synovial cell sarcoma Hematologic: Leukemia Skin: Melanomas Lynch Syndrome MSH2, MLH1, CNS: High Grade Glioma MSH6, PMS2, Abd: Colorectal, Gastric, Pancreatic ca 51 PMS1 GU: Endometrial, Urinary tract ca Constitutional MSH2, MLH1, CNS: High grade gliomas Mismatch Repair MSH6, PMS2, Abd: Colon ca 9 Deficiency PMS1 Hematologic: Leukemia, Lymphoma Abbreviations: BRRS: Bannayan–Riley–Ruvalcaba syndrome, Ca: carcinoma, JMML: juvenile myelomonocytic leukemia, MPNST: malignant peripheral nerve sheath tumor, SCCOHT: small cell carcinoma of the ovary, hypercalcemic type, WAGD: Wilms, aniridia, genitourinary abnormalities, developmental delay, PROS: PIK3CA-related Overgrowth Spectrum
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