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Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20–33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair–deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Supplementary Table 3 shows types of surgical resection

Supplementary Table 1 shows number of TAP cases per site

Supplementary Table 2 shows individual case-level data (clinical history, genetic testing, secondary cancers)

Purpose:The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.Experimental Design:A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.Results:Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).Conclusions:When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Supplemental Table 1: Clinical Characteristics, Treatment, and Recurrence Rates of of Patients with Stage II SBA Supplemental Table 2. Germline variants among SBA patients

Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Results: Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Background Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. Objective To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. Design, setting, and participants We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. Outcome measurement and statistical analysis The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher’s exact or χ2 test). Results and limitations Of 232 patients with early-onset RCC, 50% had non–clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non–RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non–clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes was 0% and 9.9%, respectively. Conclusions Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. Patient summary In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

INTRODUCTION AND OBJECTIVE:Prior studies have found 14% to 24% of patients with urothelial carcinoma (UC) have germline pathogenic/likely pathogenic (P/LP) variants, most of which are in moderate/h...

523 Background: Despite being a rare cancer, upper tract urothelial carcinoma (UTUC) is the third most common core cancer associated with Lynch syndrome (LS) after colorectal and endometrial cancers. Yet, there is no established guideline to identify patients with UTUC who are at risk of carrying germline mutations in LS-associated genes. The objective of this study is to define selection criteria for patients with UTUC for LS screening. Methods: We retrospectively identified patients with UTUC who underwent germline sequencing of ≥77 cancer susceptibility genes using next generation sequencing (NGS) as part of a prospective matched tumor-normal genomic profiling initiative from 04/2015 to 04/2021. Mismatch repair protein status was evaluated by immunohistochemical (IHC) staining for MMR genes MSH2, MSH6, MLH1, and PMS2. Microsatellite instability (MSI) status was determined using NGS. Diagnostic performance of clinical and tumor-based screening criteria was assessed by the presence of germline pathogenic/likely pathogenic variants (PGVs) in MMR genes. Results: A total of 232 patients with UTUC underwent germline testing; median age of diagnosis was 67 years (interquartile range 59 – 73). Of these patients, 70% were male, 43% had UTUC diagnosed before the age of 65, 85% had high grade UTUC,12% had bilateral UTUC, 11% had metastasis at diagnosis, 10% and 31% had personal and family history of LS-associated cancers, respectively. PGVs in moderate or high-penetrance genes were identified in 31 (13%) patients including 6 (3%) in BRCA1/ 2 and 21 (9%) in MMR genes (13 MSH2, 4 MSH6, 4 MLH1). A total of 10/21 (48%) patients with MMR PGVs developed UTUC as their first cancer diagnosis. Of patients with MMR PVGs, 15/16 (94%) had MMR-deficient tumors and 12/18 (67%) had MSI-high tumors. Personal and family history of LS core cancers (p < 0.001), age of diagnosis < 65 (p = 0.008), MSI-high (p < 0.001), and MMR-deficiency (p < 0.001) were associated with MMR carrier status. Female gender (p = 0.7), HG UTUC (p = 0.5), and bilateral UTUC (p = 0.7) were not associated with MMR PGVs. Current NCCN genetic referral criteria for Lynch syndrome has high specificity in identifying patients with LS (100%) but missed 11/21 (52%) patients with UTUC and MMR PGVs. Conclusions: Current genetic referral guidelines for Lynch syndrome may miss a significant portion of patients with LS-associated UTUC. UTUC tumor should be investigated for MMR protein and MSI status with IHC or next generation sequencing methods to augment LS-screening of patients with UTUC and inform systemic treatment selection.

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.

296 Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.