Genetic Cancer Predisposition Research Articles

Synchronous endometrial and minor salivary gland carcinomas – role of molecular diagnostics amid lack of clinical suspicion

Abstract Introduction/Objective Synchronous malignancies account for 3-5% of all tumor diagnoses but can be challenging to detect if one or both tumors are rare histologic subtypes and clinical suspicion is lacking. Molecular diagnostics are critical for accurate diagnosis in these difficult cases to guide appropriate patient care. Methods/Case Report We report the case of a 49-year-old female who was diagnosed with a high-grade, mixed- histology endometrial adenocarcinoma a few years back. She was found to have hilar and mediastinal nodal carcinoma of uncertain differentiation a couple of months after her initial diagnosis, clinically labelled as metastatic endometrial carcinoma. Following neoadjuvant chemotherapy, her hysterectomy showed complete pathologic response, and was found to be POLE ultramutated on NGS. Follow-up PET scan in 2023 showed progression of hilar/endobronchial thickening, as well as interval increase in size of mediastinal nodes, again presumed to be endometrial metastases, despite the POLE mutant status. Repeat sampling was performed from both the sites, along with comprehensive molecular profiling. Cytology from the nodes and surgical pathology from the endobronchial lesion showed similar morphology consisting of hyperchromatic basaloid cells in cribriform arrangement with tubular structures containing myxoid stromal material, negative for PAX-8, ER, p40, and TTF1 immunostains, inconsistent with endometrial metastasis. Molecular studies including FISH and NGS showed MYB1::NFIB fusion characteristic of adenoid cystic carcinoma and absence of POLE mutation, definitively refuting the clinically suspected progression of endometrial metastasis. Molecular testing confirmed that the endobronchial tumor and mediastinal nodal involvement were caused by a second primary, distinct from her POLE-ultramutated endometrial carcinoma which disappeared with chemotherapy. Her extended molecular workup also revealed a pathogenic mutation in BRIP1, suggesting a genetic cancer predisposition syndrome requiring referral for genetic counseling. Results (if a Case Study enter NA) NA Conclusion Molecular pathology is an invaluable tool for unravelling diagnostic complexity. Pathologists must integrate cytomorphology, molecular genetics and knowledge of cancer biology to steer the clinical teams towards the best patient care.

Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.

Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Women’s preferences for genetic screening in routine care: A qualitative study

ObjectiveExamine decision-making regarding when women would prefer to receive reproductive carrier and cancer predisposition screening and from what clinician. Methods20 women completed in-depth interviews via Zoom exploring their views on the provision of reproductive carrier and cancer predisposition screening. Our analysis identified themes related to what informs women’s preferences for when they would like to receive a genetic screening offer and by which clinician. ResultsParticipants’ responses to questions about when they would be interested in receiving genetic screening were best understood through the lens of the Extended Parallel Process Model. Specifically, personal utility of the information, a woman’s family health history and cost were key factors in decision-making. Women considered their clinician’s knowledge and their trust in and relationship with the clinician when deciding from whom they would prefer to receive an offer of genetic screening. ConclusionOB/GYN clinic patients may accept an offer of genetic screening from a knowledgeable and trusted clinician for carrier and cancer predisposition screening preconceptionally or prenatally. Practice implicationsIntegrating genetic reproductive and cancer predisposition screening into the care provided to reproductive age OB/GYN patients may be acceptable to this population.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

HGG-28. THE IMPACT OF CMMRD IN HIGH-GRADE GLIOMA PATIENTS, A RETROSPECTIVE ANALYSIS OF 7 YEARS IN LMIC; AN IRRDC STUDY

Abstract BACKGROUND Constitutional mismatch repair (MMR) deficiency (CMMRD) is a genetic cancer predisposition syndrome presenting among children and young adults. This study is the first to evaluate CMMRD prevalence among high-grade glioma patients in Pakistan, a country with high consanguinity rates. METHODS We reviewed data of patients younger than 18 diagnosed with pediatric high-grade glioma, anaplastic astrocytoma, and diffuse midline glioma with CMMRD testing between 2016 and 2023. Tumor slides of all included cases were prepared and sent to Sick Kids Toronto to review the MMR protein stains via multi-gene panels. RESULTS Forty-five patients were identified (62.3% females); median age of 11. Headache (88.9%) was the most common symptom, followed by vomiting (60%) and seizures (37.8%); median duration of symptoms was two months. Histopathology revealed 73.3% pediatric high-grade glioma, 22.2% Anaplastic Astrocytoma, and 4.4% Diffuse Midline Glioma. Thirty-six patients (80%) had a cerebral tumor, 13.3%, and 6.7% had a posterior fossa and midline tumor, respectively. CMMRD was positive in 15 of 45 patients (33.3%). Eight patients (53.4%) had CMMRD with loss of PMS 2, two (13.3%) had loss of PMS 2 and MLH 1, two (13.3%) had loss of MSH 2, two (13.3%) had loss of MSH 6, and only one patient had loss of MSH 6 and MSH 2. Consanguinity correlated with CMMRD (P=0.045), but family history of malignancy was not significant (P=0.202). One-year overall survival of all patients, with a median follow-up of 4.8 months, was 44.4 %, whereas 1-year overall survival compared to CMMRD was 33.3%, with a median follow-up of 7.2 months (P=0.616) CONCLUSION We found high prevalence of CMMRD among pediatric high-grade glioma patients and patients with consanguinity. The findings of our study emphasize the importance of genetic testing and counseling. Timely accurate diagnosis is essential as decreased response to conventional treatment regimens may increase disease burden.

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions.

The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

Perceived transition readiness among adolescents and young adults with neurofibromatosis type 1 and plexiform neurofibromas: a cross-sectional descriptive study.

Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors, requiring care from birth through adulthood. Adolescents and young adults (AYAs) with NF1 face several barriers to transition from pediatric to adult care. This cross-sectional study aimed to assess transition readiness in this population and to evaluate relationships between specific NF1 symptoms and transition readiness. AYAs (aged 16-24) enrolled in existing studies related to NF1 were eligible. AYAs and their parents completed measures of transition readiness (Transition Readiness Assessment Questionnaire version 4 [TRAQ-4]), and AYAs also completed a transition readiness interview (UNC TRxANSITION). Thirty-eight AYAs (mean age = 19.95 ± 2.68 years) participated in the study. Average TRAQ scores indicated that AYAs were still learning Self-Management skills (M = 3.37, SD = 1.08) and Self-Advocacy skills (M = 3.98, SD = 0.67). Older AYAs had higher TRAQ scores for Self-Management (r = 0.70, p < .001) and Self-Advocacy (r = 0.41, p = .011) than younger AYAs. Parents and AYAs had similar TRAQ scores. About one third of AYAs (37.8%, n = 14) expressed uncertainty about how NF1 might affect them in the future. The remaining AYAs mostly expressed concerns regarding tumor growth, pain, or cancer. In this small study, preliminary findings suggest that AYAs with NF1 express confidence in many areas of transition readiness but continue to require support, particularly with Self-Management skills. Given the gaps in understanding of future health risks, AYAs with NF1 would benefit from early assessment, psychoeducation, and support for transition readiness to adult care.

Quality of cancer family history taking in pediatric solid tumor patients.

10045 Background: Approximately 10% of childhood solid tumors occur in individuals with a cancer genetic predisposition. Identifying cancer predisposition permits interventions for prevention and early detection of future cancers in the child and their affected family members and may have other important medical care implications. The American Society of Clinical Oncology (ASCO) guidelines recommend reviewing family history (FHx) to identify high-risk patients who should be offered genetic testing. To our knowledge, adherence to ASCO guidelines by pediatric oncology providers (POPs) has not been studied. Methods: Retrospective chart review of solid tumor patients &lt;18 years of age referred for genetic counseling 1/1/2017-1/31/2019. POP and genetic counselor (GC) FHx documentation was assessed for adherence with the ASCO minimum quality metrics: 2 generation pedigree, patient ethnicity, cancer genetic testing results in relatives (GTRR), and cancer type, age at diagnosis, and lineage (maternal/paternal) for each relative with cancer (RWC). Comparisons of FHx quality between POPs and GCs were evaluated with 1-sided t-tests. Ethnicity was considered assessed if both maternal and paternal ethnicities were documented. GTRR was considered assessed if the results of all relatives who had undergone genetic testing were noted. Cancer type, age at diagnosis, and lineage were considered assessed if they were checked for all RWCs. Whether or not the child underwent genetic testing and their testing results were also documented. Results: Of 129 eligible patients, 102 underwent germline genetic testing. Twelve (12%) had pathogenic alterations in cancer predisposition genes. The POP failed to document FHx in 20 patients (16%), including 2 with pathogenic germline alterations. The POP missed first/second degree RWCs in 32 of 88 patients with RWCs (36%). GCs achieved &gt;99% on each of the 6 ASCO quality metrics, whereas POPs performed significantly more poorly (Table). In patients with RWCs, GCs achieved all 6 metrics in more cases than POPs (99% vs. 3%, p&lt;0.001). Conclusions: POPs performed significantly worse than GCs in documenting family history compliant with ASCO minimum family history guidelines, raising concern for missed genetic cancer predisposition syndrome diagnoses in those not referred to a GC. Routine referral of pediatric solid tumor patients to a GC for family history review and interventions to improve the quality of family history taking by POPs may improve germline cancer predisposition detection, improving care of both patients and their affected family members. [Table: see text]

Implementing a germline testing program using fingernail specimens for patients with hematologic malignancies and initial clinical findings.

10632 Background: About 5-20% of hematologic malignancies (HM) occur in the setting of a genetic cancer predisposition syndrome. Additionally, overt constitutional syndromes involving multiple systems may also predispose to HM. The spectrum of cancer predisposition in patients with HM has been limited partially due to the difficulty of germline sample ascertainment from patients with liquid tumors as skin biopsies and fibroblast cultures are often required for testing. Methods: Hematologic malignancy patients enrolled in Memorial Sloan Kettering Cancer Center’s institutional 12-245 study who were having somatic testing performed on their tumor were given the option to consent to germline testing using fingernail specimens. The validated germline assay using nails as a sample type was approved as a clinical test by the New York State Department of Health. Samples were analyzed using a custom panel consisting of 82 cancer predisposition genes. Single nucleotides, insertions deletions, and copy number variants were detected using our analytic pipeline and analyzed according to ACMG criteria for pathogenicity. Only pathogenic and likely pathogenic germline variants (gPV) were returned. Results: Among 86 HM patients (acute myeloid leukemia, n = 19; myelodysplastic syndrome, n = 16; acute B lymphoblastic leukemia, n = 9; acute T-cell leukemia, n = 4; mixed phenotypic acute leukemia, n = 1; chronic lymphocytic leukemia, n = 7; hairy cell leukemia, n = 1; chronic myeloid leukemia, n = 4; chronic myelomonocytic leukemia, n = 1, non-Hodgkin lymphoma, n = 12; Hodgkin lymphoma, n = 8; and multiple myeloma, n = 4), gPV were detected in 16 % (14/86). Heterozygous gPV identified in high/moderate penetrant genes included 2 BRCA1, 2 ATM, 1 PALB2, and 3 CHEK2. Monoallelic carriers for homozygous disease included 2 MUTYH and 1 MSH3. Biallelic gPV were identified in 3 patients (1 FANCA, 1 ATM, 1 MSH6); the patients with Fanconi anemia (age 25) manifesting with MDS and constitutional mismatch repair deficiency (age 13) presenting with T-cell lymphoblastic lymphoma had not been previously diagnosed with these conditions and did not have obvious clinical features outside of their cancer diagnosis. In all 3 patients, identification of an autosomal recessive syndrome impacted therapeutic planning. Conclusions: Our study demonstrates the feasibility of utilizing nails, a non-contaminated germline sample source, for HM predisposition with a significant proportion of pediatric and adult HM patients identified to harbor gPV in a cancer predisposition gene. Autosomal recessive diseases should be considered not only in pediatrics but also adult patients and requires confirmation of allele segregation in parents. Our data also demonstrate the importance of gPV in HM for therapeutic planning.

A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children

PurposeClinical checklists are the standard of care to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. MethodsWe assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding exome sequencing analysis in an unselected single-center cohort of 139 child-parent data sets. ResultsIn total, one-third of patients had a clinical indication for genetic testing according to current recommendations, and 10.1% (14 of 139) of children harbored a cancer predisposition. Of these, 71.4% (10 of 14) were identified through the clinical checklist. In addition, >2 clinical findings in the checklist increased the likelihood to identifying genetic predisposition from 12.5% to 50%. Furthermore, our data revealed a high rate of genetic predisposition (40%, 4 of 10) in myelodysplastic syndrome cases, while no (likely) pathogenic variants were identified in the sarcoma and lymphoma group. ConclusionIn summary, our data show high checklist sensitivity, particularly in identifying childhood cancer predisposition syndromes. Nevertheless, the checklist used here also missed 29% of children with a cancer predisposition, highlighting the drawbacks of sole clinical evaluation and underlining the need for routine germline sequencing in pediatric oncology.

Osteosarcoma.

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.

Benign goiters requiring thyroidectomy as the signal for PTEN hamartoma tumor syndrome diagnosis.

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic cancer and tumor predisposition syndrome. Due to the wide spectrum of clinical manifestations and variable age at onset, the pathways leading to a PHTS diagnosis are difficult and highly variable. Many patients were found to have PHTS after a cancer diagnosis, missing the opportunity of prevention or enhanced cancer screening. This retrospective study evaluated a PHTS cohort followed in a high-risk surveillance clinic in a comprehensive cancer institution. A significant portion of the patients (60.9%, 14/23) had at least one cancer diagnosis (average age 34.6 years at diagnosis). A significant portion (78.3%, 18/23) were affected with clinically significant goiters (age 27.9 years), and many (60.9%, 14/23) had partial or total thyroidectomy (age 27.1 years). The average age at goiter diagnosis or thyroidectomy is younger than a cancer diagnosis. In 12 individuals who were affected with clinically significant goiter and cancer, all cancers were diagnosed after the thyroid disease (6.3 years). As clinically significant thyroid nodules in childhood or early young adulthood are common in PHTS, but uncommon for general population, these early onset thyroid nodules may alert the clinician to initiate PHTS-targeted evaluation and genetic testing.

Genetic tumor risk syndromes : Human genetic aspects for radiologists

Most malignant diseases develop sporadically. However, asignificant proportion of cancers are based on genetic predispositions. In this case, cancer develops as aresult of causal germline variants. In general, the associated diseases are called genetic tumor risk syndromes or cancer predisposition syndromes. Recognition of these syndromes is in the interest of those affected, as well as of their relatives, as this may have influence on immediate therapy or aftercare. In the course, risk-adapted surveillanceor risk-reducing operations may be indicated. Taking into account four signs (i.e., past medical history, characteristic tumors or suspicious age of onset, somatic alterations of the tumors, and family history), radiologists can contribute to the identification of patients with cancer predisposition. Besides appraisal of screening images, the expertise of radiologists is especially needed to develop and reevaluate risk-adapted surveillance programs.

EPCO-27. REVEALING TUMOR HETEROGENEITY AND IMMUNE MICROENVIRONMENT IN NF-1 GLIOMA BY SINGLE-CELL GENE EXPRESSION PROFILING

Abstract Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.

Unpaved roads: How the DNA damage response navigates endogenous genotoxins

Accurate DNA repair is essential for cellular and organismal homeostasis, and DNA repair defects result in genetic diseases and cancer predisposition. Several environmental factors, such as ultraviolet light, damage DNA, but many other molecules with DNA damaging potential are byproducts of normal cellular processes. In this review, we highlight some of the prominent sources of endogenous DNA damage as well as their mechanisms of repair, with a special focus on repair by the homologous recombination and Fanconi anemia pathways. We also discuss how modulating DNA damage caused by endogenous factors may augment current approaches used to treat BRCA-deficient cancers. Finally, we describe how synthetic lethal interactions may be exploited to exacerbate DNA repair deficiencies and cause selective toxicity in additional types of cancers.

Abstract 5244: Radiation-associated sarcoma exhibits worse outcomes than sporadic sarcoma

Abstract Background: Radiation-associated sarcoma (RAS) occurs following ionizing radiation exposure from a therapeutic or environmental source. Because half of all cancer patients will receive radiation therapy (RT), there is a need to understand the etiology of radiation-induced sarcomas, as these cancers are thought to exhibit worse outcomes than their sporadic counterparts. Methods: A retrospective single-center analysis of sarcoma patients treated from 2013-2019 was conducted. Univariate and survival analyses were used to distinguish the characteristics of RAS and sporadic sarcoma (SS), and further assess differences in disease presentation, cancer treatment, and survival between the two groups. Results: The incidence of RAS during the study period was 6%. Breast (25%), prostate (25%) and colorectal (15%) cancers were the most common primary tumors associated with RAS development. There was substantial variation in the characteristics of the two groups, with noted differences in the histologic compositions, clinical stage at presentation, and overall survival (Table 1). The most frequent RAS histologies were angiosarcoma (30%), leiomyosarcoma (25%) and undifferentiated pleomorphic sarcoma (20%), while the most frequent SS subtypes were liposarcoma (15.5%), carcinosarcoma (13.5%) and leiomyosarcoma (11.9%). No patients with RAS had a known genetic cancer predisposition. A higher percentage of RAS patients presented at later clinical stages, as 75% of all RAS cases versus 41.9% of all SS cases were diagnosed at stage III/IV (p=0.004). RAS also exhibited overall worse outcomes, as the 5-year survival was significantly decreased compared to SS (32.6 vs 60.3%, p=0.027). Conclusion: Our study identifies marked differences in the disease characteristics and clinical outcomes of RAS and SS. Further research into cancer predisposition, biomarkers of risk, and molecular pathways of disease is essential to provide individualized care to patients with RAS. Table 1. Summary of Sporadic Sarcoma and Radiation-Associated Sarcoma Characteristics Sporadic Sarcoma Radiation-Associated Sarcoma P-Value Count 310 20 Median Age at Diagnosis (Years) 58.51 (0.02-87.74) 68.81 (48.09-84.19) 0.003 Location Trunk 109 (35.2%) Trunk 10 (50.0%) Lower Extremity 97 (31.3%) Lower Extremity 2 (10.0%) Head/Neck 36 ( 11.6%) Retroperitoneal 4 (20.0%) Other 68 (21.9%) Other 4 (20.0%) Histologic Subtype Liposarcoma 48 (15.5%) Angiosarcoma 6 (30.0%) Carcinosarcoma 42 (13.5%) Leiomyosarcoma 5 (25.0%) Leiomyosarcoma 37 (11.9%) UPS 4 (20.0%) Chondrosarcoma 36 (11.6%) Liposarcoma 3 (15.0%) Other 147 (47.4%) Other 2 (10%) Clinical Stage I &amp; II 146 (47.1%) 4 (20.0%) 0.01 III &amp; IV 130 (41.9%) 15 (75.0%) 0.004 Unknown 34 (11.0%) 1 (5.0%) Treatments Surgery 244 (78.7%) 12 (60.0%) 0.12 Radiation 91 (29.4%) 10 (50.0%) 0.95 Chemotherapy 105 (33.6%) 7 (35.0%) 0.35 Status at Follow-Up NED 139 (44.8% ) 6 (30.0%) AWD 74 (23.9%) 3 (15.0%) Deceased 97 (31.3%) 11 (55.0%) Five-Year Survival 60.3% 32.6% 0.027 Citation Format: Abigail Raynor, Amy Oh, Wen-I Chang, Joshua Honeyman. Radiation-associated sarcoma exhibits worse outcomes than sporadic sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5244.

Abstract 5220: The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening

Abstract Beckwith-Wiedemann Spectrum (BWSp) is the most common (epi)genetic cancer predisposition disorder. BWSp has a heterogeneous clinical presentation and is caused by epigenetic changes at two regions on chromosome 11p15. These epigenetic changes occur post-zygotically leading to a mosaic distribution among tissues. Clinical molecular testing usually starts with blood; however, we and others have demonstrated that positive molecular testing rates are increased if testing is performed on affected tissues. Clinical and molecular diagnosis is important because patients with BWS are at risk for development of embryonal tumors (Wilms tumor (WT), hepatoblastoma (HB), and neuroendocrine tumors). Formal surveillance guidelines were published in 2017 as part of a United States-based cancer predisposition effort that recommended alpha fetoprotein and complete abdominal ultrasound screening for all patients with BWSp until 4 years of age for HB and renal ultrasound screening until 7 years of age for WT. In contrast, the European-based BWS international consensus group (BWS-ICG) applied stratified cancer screening recommendations based on (epi)genotype. In the present study, we investigated cancer development rates and epigenotype profiles associated with cancer in patients diagnosed with BWSp. We present a series of patients with history of WT, HB, and/or neuroendocrine tumors to highlight that there can be differing BWSp epigenotype profiles in tumor and adjacent normal tissue compared to blood, demonstrating the presence of multiple cell populations with distinct epigenetic changes within patients. These distinct changes show that more than one epigenetic alteration in the chromosome 11p15 region can be present in a single tissue type. These findings suggest that the epigenetic classification in blood alone should not be used to stratify cancer risk in BWSp. Additionally, the mild BWSp clinical phenotype and low BWS-ICG clinical scores for these patients highlight that some patients present with few external features. Therefore, neither blood epigenotype nor external phenotype can help inform an individual’s unique tumor risk. This work further suggests that the BWS-ICG tumor risk stratification system cannot be applied to the full Beckwith-Wiedemann Spectrum due to the emerging epigenetic and phenotypic landscape of patients diagnosed with BWSp. These results support a recommendation of universal tumor screening for all patients diagnosed with even mild BWSp phenotypes and/or a 11p15 epigenetic abnormality. Citation Format: Kelly A. Duffy, Evan R. Hathaway, Mallory E. Byrne, Andrew M. George, Timothy Mcelroy, Suzanne P. MacFarland, Garrett M. Brodeur, Jennifer M. Kalish. The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5220.

Using health information technology to improve collection of family cancer history: prospective randomized trial of web-based tool in a gynecologic oncology outpatient clinic

<h3>Objectives:</h3> In the US there are approximately 4 million individuals with a genetic cancer predisposition syndrome, however, the majority are not aware and cannot benefit from genetically-targeted cancer prevention. Family cancer history (FCH) can identify high risk patients and triage them to genetic assessment, however there is wide variability in accuracy, breadth and strategies for FCH collection. We aim to evaluate whether a web-based tool (WBT) can result in improved quality of FCH versus standard FCH collection via face-to-face interview. <h3>Methods:</h3> All patients scheduled for a gynecologic oncology new patient visit between 9/2019-9/2020 were offered enrollment in an institutional review board-approved prospective trial. Patients were randomized to one of three arms: 1) standard of care FCH collection during the interview, 2) WBT administered at home prior to the visit, 3) WBT administered in the office prior to the visit. The primary endpoint was evaluation of FCH quality based on established quality measures. Chi-square test was used to compare FCH quality between intervention arms and ANOVA test for the number of relatives/generations in the pedigree. A Bonferroni correction was used to account for multiple comparison testing. <h3>Results:</h3> A total of 100 patients were enrolled. The mean age was 56.2 years (SD 15.2). The WBT was completed successfully by 67% (22) of patients randomized to home administration vs 94% (31) randomized to office administration (P=0.01). Patients cited the following reasons for failure to complete the WBT at home: difficulty with technology, concern about privacy and forgetting about the WBT invitation. In the intention-to-treat analysis, office WBT collection resulted in significantly higher quality FCH vs the control and home arms (Table 1). The WBT resulted in significantly greater mean number of relatives included in the pedigree (Arm 1 - 3.9 [SD 3.0], Arm 2 - 32.4 [SD 16.8], Arm 3 - 29.0 [SD 18.3], P<0.001) and significantly greater number of included generations (2.2 [SD 0.9], 3.9 [SD 0.4], 3.7 [SD 0.6], P<0.001). Patient age, race, ethnicity, and personal/family cancer history were not associated with FCH quality. When excluding patients who could not access the WBT at home, there were no differences in FCH quality when WBT was completed at home vs in the office. A total of 39 patients utilizing the WBT (74%) completed a satisfaction survey following the office visit; 38 (97%) reported that the WBT was easy to understand and 30 (77%) reported being satisfied with the tool. <h3>Conclusions:</h3> FCH collection is an exciting application of information technology in the current healthcare setting with a growing emphasis on cancer genetics, disease prevention and thoughtful use of WBTs. In our cohort of gynecologic-oncology patients, a WBT resulted in significantly higher quality and more comprehensive family cancer pedigrees. With the COVID-19 pandemic inspired drive to minimize in-office time, future studies must assess strategies to improve patient engagement with WBT at home prior to the visit.

Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.