Buchanan DD, Georgeson P, Walker R
… +14 more, Joo JE, Clendenning M, Como J, O'Keeffe R, Prisc A, Chu YL, Jenkins MA, Rosty C, Winship IM, Macrae FA, Ip E, Harris R, Goodwin A, Mahmood K
Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic feature...Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.
Objectives of the study were to determine the success, complication and recurrence rate of endoscopic papillectomies in familial adenomatous polyposis (FAP) patients. Ampullary adenoma is frequent in familial adenomatous...Objectives of the study were to determine the success, complication and recurrence rate of endoscopic papillectomies in familial adenomatous polyposis (FAP) patients. Ampullary adenoma is frequent in familial adenomatous polyposis (FAP) patients. Endoscopic papillectomy is technically demanding for laterally spreading ampullary adenomas and bleeding, perforation and pancreatitis represent typical complications. 40 FAP patients undergoing endoscopic papillectomy were retrospectively analyzed. Data on periprocedural complications, histopathology, resection techniques and success were collected. Endoscopic papillectomy was performed in 21 male and 19 female patients. Mean adenoma size was 14 mm (8-40 mm). Additional mucosal resection was performed in 45%. Immediate and delayed bleeding occurred in 33% (n = 13) and 13% (n = 5), respectively. Bleeding was associated with male sex and pancreatic endoprosthesis. Endoscopically manageable perforation occurred in 2 patients. Acute pancreatitis occurred in 25% (n = 10) and was significantly associated with female sex. Histopathology revealed papillitis in 5% (n = 2), adenoma with low-grade dysplasia in 73% (n = 29), high-grade dysplasia in 13% (n = 5), and adenocarcinoma in 5% (n = 2). Cumulative recurrence-free resection was achieved in 94% (n = 33/35) after a mean of 1.4 procedures at a median follow-up of 591 days (range 15-2605). Endoscopic papillectomy shows a high clinical success in FAP patients even with laterally spreading adenoma. Adenoma recurrence can be successfully treated with a limited number of reinterventions.
NF2-related schwanomatosis (NF2-SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bi...NF2-related schwanomatosis (NF2-SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bilateral eighth nerve tumours with von Recklinghausen disease (currently Neurofibromatosis 1, NF1) in 1917 the literature was confusing for much of the 20th century. Even when the conditions were separated officially in 1987 (with separate localisation of the genes), NF2-SWN remained classified as a neurofibromatosis despite the tumours pathognomonic for NF1, neurofibromas, not being a feature of NF2-schwannomatosis. It is only in 2022 that NF2-SWN was correctly delineated as a schwannomatosis. The epidemiology of NF2-SWN has only been possible to delineate after the separation of NF2-SWN from the much more frequent nerve sheath predisposing tumour condition NF1. Two research groups have published on the birth prevalence and population prevalence of NF2-SWN in the UK and Finland. The most highly ascertained assessment of NF2-SWN cases from the Manchester region of England (population 4.8 million) gave a diagnostic prevalence of 1 in 50,500 and calculated birth prevalences of 1 in 27,956 respectively. However, an updated prevalence across England in 2024 (population 55 million) gave a prevalence of at least 1 in 58,000. NF2-SWN usually presents with bilateral vestibular schwannoma, but can present with meningioma or spinal tumour or ophthalmic features before a VS diagnosis or with a unilateral VS and other tumours and rarely with a unilateral VS alone. Molecular testing is now extremely helpful in confirming the diagnosis of mosaic (present in up to 50% of de novo cases) versus germline NF2 and distinguishing from other tumour predisposition conditions especially in childhood or cases with less common presentation. This chapter summarises the clinical epidemiology of NF2-SWN differentiating the condition from the overlapping non NF2-SWN.
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for familial adenomatous polyposis (FAP) in our institution. Stapled and hand-sewn IPAA differ in the amount o...Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for familial adenomatous polyposis (FAP) in our institution. Stapled and hand-sewn IPAA differ in the amount of retained rectal mucosa, influencing both adenoma risk and functional outcomes. In this retrospective cohort study, we compared oncological and functional outcomes between the two techniques. Consecutive patients with FAP who underwent RPC with IPAA at Seoul National University Hospital between 1994 and 2022 were included. The ATZ adenoma and cancer occurrence, operative time, and anorectal functional outcomes were compared between hand-sewn and stapled anastomosis groups. The cumulative incidence risk of adenoma recurrence was compared using the log-rank test. 89 patients were analyzed: 32 underwent hand-sewn and 57 underwent stapled IPAA. Median follow-up was 100 months in the stapled group and 79 months in the hand-sewn group. Stapled IPAA was associated with shorter operative time (220.6 vs. 332.9 min, p < 0.001), lower diverting ileostomy rate (78.9% vs. 96.9%, p = 0.027), and lower Wexner incontinence scores (1.54 vs. 3.43, p = 0.009). Adenomas or carcinomas at the ATZ were identified in 29.2% of patients, with a higher 5-year adenoma recurrence in the stapled group (20.1% vs. 3.2%, p = 0.02). Most adenomas were successfully managed endoscopically, with no cancer progression in the stapled group. Two cancers occurred in the hand-sewn group during long-term follow-up. Stapled IPAA offers advantages in operative efficiency and anorectal function, with higher adenoma recurrence manageable under surveillance. These findings suggest stapled IPAA may be a reasonable surgical option for FAP when coupled with diligent follow-up.
Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by a pathogenic germline variant in one of the mismatch repair (MMR) genes. There is a lack of evidence supporting surveillance for urothelial car...Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by a pathogenic germline variant in one of the mismatch repair (MMR) genes. There is a lack of evidence supporting surveillance for urothelial carcinoma (UC) in LS, however several surveillance strategies have been proposed in recent years. This has led to a variety of practices. This study reports on the current practice for UC surveillance in LS in the Netherlands. Individuals with LS from two university hospitals and a large comprehensive cancer center were selected. Data on UC surveillance and UC diagnoses were recorded. Cumulative incidence was calculated. Of 235 individuals with LS, 40% underwent UC surveillance. Individuals with a pathogenic MSH2 variant were under surveillance significantly more often than those with other pathogenic variants. Of the individuals who underwent surveillance 10% had annual testing and continued surveillance up until the last known follow up date. None of the surveillance tests led to a UC diagnosis. Of eight patients with UC, two were under active surveillance, but were diagnosed due to macroscopic hematuria after normal cytology results. Cumulative UC incidence was 9% at age 75. Currently, most individuals with LS in this cohort are not part of a surveillance program for UC. Cumulative UC risk is high, up to 9%, and none of the UC were detected by surveillance. Given the lack of evidence that a suitable surveillance test is available, we do not recommend surveillance for UC.
Only 67% of eligible patients with breast cancer currently undergo genetic testing. Mainstream genetic testing (i.e. healthcare professionals (HCPs) from outside the genetics field providing genetic counselling), also re...Only 67% of eligible patients with breast cancer currently undergo genetic testing. Mainstream genetic testing (i.e. healthcare professionals (HCPs) from outside the genetics field providing genetic counselling), also referred to asmainstreaming, leads to increased uptake of genetic testing. Unlike surgical oncologists, medical oncologists have not yet widely adopted mainstreaming. This study aims to identify barriers and facilitators for HCPs, in particular medical oncologists, in advancing the implementation of mainstreaming. Structured interviews were conducted with HCPs (predominantly medical oncologists) using the Constructive Technology Assessment (CTA) framework. Participants were recruited from all regions of the Netherlands, ensuring representation from academic medical centres, teaching hospitals and general hospitals. The interview data was analysed using thematic analysis. In this qualitative study, 12 medical oncologists, three nurse practitioners, three clinical geneticists, two clinical laboratory geneticists and one representative of a health insurer were interviewed. Lack of time and limited knowledge were the most commonly mentioned barriers, whilst effective cross-departmental collaboration and education were the most important facilitators. For medical oncologists specifically, financial compensation for the increased workload and the increasing importance of genetic testing for guiding therapy choices were found to be encouraging factors. This study identified several barriers and facilitators to mainstreaming being implemented by medical oncologists. Education to strengthen oncologists' skills in discussing germline genetic testing may address knowledge gaps and time barriers. Alongside cross-departmental collaboration, these strategies could streamline genetic testing pathways. Further research should evaluate their implementation and effects on patient experience and equitable access.
Early-onset breast cancer in a woman prompted referral for genetic counseling, due to suspected hereditary cancer predisposition. After collecting a detailed personal and family medical history and providing comprehensiv...Early-onset breast cancer in a woman prompted referral for genetic counseling, due to suspected hereditary cancer predisposition. After collecting a detailed personal and family medical history and providing comprehensive pre-test counseling, the patient consented to a multigene panel test for breast cancer susceptibility. Genetic analysis revealed a germline variant, c.662 C > T p.(Pro221Leu), in the STK11 gene, initially classified as a variant of unknown significance (VUS). Given the possibility of Peutz-Jeghers syndrome (PJS), a thorough review of the patient's extended family history was undertaken to identify clinical features consistent with the syndrome. The maternal grandmother's lineage revealed a striking aggregation of malignancies, including eight cases of breast cancer (ages 34-73), one suspected gastric cancer before age 50, and five individuals with colorectal polyps. On the maternal grandfather's side, nine breast cancer cases (ages 34-77), one childhood skin cancer, and one endometrial cancer at age 56 were described. Segregation studies in multiple relatives demonstrated co-segregation of the STK11 variant with disease. This evidence supported the reclassification of the STK11 c.622 C > T p.(Pro221Leu) variant as likely pathogenic. Consequently, carriers were enrolled in syndrome-specific surveillance protocols for PJS. This case underscores the essential role of comprehensive clinical and familial assessment, alongside segregation studies, in refining variant interpretation and enabling personalized, syndrome-specific management strategies.
This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant-NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)-in Mexican individuals. Although this varia...This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant-NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)-in Mexican individuals. Although this variant is frequently detected through multi-gene panel testing, limited data on its associated cancer risks complicates genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients who underwent multi-gene panel testing between August 2015 and August 2024 due to suspected hereditary cancer syndromes. Among them, 58 CHEK2 p.(Leu236Pro) carriers with confirmed cancer diagnoses were identified. Geographical clustering was observed, with 81% of patients originating from central Mexico, suggesting a possible founder effect. Ten distinct clinical indications for genetic testing were identified, with hereditary breast and ovarian cancer (HBOC) syndrome being the most common (74.1%). The mean age at first diagnosis among carriers was 43.8 ± 12 years, and 61.1% of them reported a family history of cancer in first- or second-degree relatives. A second or third primary cancer occurred in 20.7% of cases. Tumors were identified in 12 anatomical sites. Breast cancer predominated (67.6%, including one male case), followed by ovarian (8.1%), prostate (6.7%), gastric (4.1%), thyroid (2.7%), and endometrial (2.7%) cancers. Lymphoma, lung, sacrococcygeal bone, colorectal, and non-melanoma skin cancers each occurred in a single patient. Significant risk association was identified only for breast, ovarian, and gastric cancers. These results highlight the need for personalized surveillance, especially for breast cancer. Incorporating CHEK2 p.(Leu236Pro) into clinical decision-making tools may enhance risk assessment in the Mexican population, but larger studies are needed to refine risk estimates and to clarify the possible founder effect.
Li-Fraumeni syndrome (LFS) is an early-onset cancer syndrome caused by pathogenic germline TP53 variants. Adolescents and young adults (AYAs) with LFS may have challenges navigating new romantic partnerships given the si...Li-Fraumeni syndrome (LFS) is an early-onset cancer syndrome caused by pathogenic germline TP53 variants. Adolescents and young adults (AYAs) with LFS may have challenges navigating new romantic partnerships given the significant effects of LFS on multiple life domains that also affect partners (e.g., reproductive decision-making). Disclosing LFS-related information to new partners may be especially difficult given the uncertainty, complexity, and chronicity of LFS. This qualitative-descriptive study aimed to explore AYAs' LFS disclosure decisions and experiences in new romantic partnerships. Participants were individuals with LFS aged 15-39 years at enrollment in a National Cancer Institute study. The analytic sample included 33 AYAs who completed at least one telephone interview. Greene's disclosure decision-making model guided thematic analysis. Participants were mostly female (67%) and married/in a long-term relationship (58%), with mean age 29 years and ≥ 1 primary cancer (61%). Key factors in LFS disclosure decision-making included perceived relevancy to partners (e.g., future children's genetic risk), partner traits (e.g., trustworthiness), and relationship quality (e.g., closeness). AYAs described LFS disclosures in new partnerships as a process. Disclosing LFS diagnosis often occurred early to fulfill a sense of moral obligation and emotionally self-protect from future rejection, while subsequent LFS disclosures depended on relationship quality and the topic's emotional valence or complexity. Partners often earned AYAs' trust by demonstrating a willingness to learn about and try to understand LFS. Clinicians and LFS communities could support AYAs by providing opportunities to discuss, normalize, and ameliorate challenges with LFS disclosures in new romantic partnerships (e.g., peer support groups, psychotherapy).
This study compares three hereditary colorectal cancer (CRC) registries-the Iranian Hereditary Colorectal Cancer Registry (IHCCR), the Singapore Polyposis Registry (SPR), and the University of Cape Town Familial CRC Regi...This study compares three hereditary colorectal cancer (CRC) registries-the Iranian Hereditary Colorectal Cancer Registry (IHCCR), the Singapore Polyposis Registry (SPR), and the University of Cape Town Familial CRC Registry-to illuminate diverse approaches to identification, management, and research across different healthcare systems. Each registry, while emphasizing patient diversity, employed unique strategies reflecting available resources and epidemiological contexts. The IHCCR, leveraging WES, revealed considerable genetic heterogeneity, including novel mutations. The SPR, a nationalized service, focused on structured surveillance and management of FAP and other polyposis syndromes, highlighting the challenges of cultural conservatism and limited public awareness. The UCT registry, initially concentrating on Lynch syndrome, expanded to encompass other hereditary CRC syndromes, revealing a high prevalence of these conditions within the South African population. All three registries encountered challenges related to access to genetic testing and early diagnosis. The registries' combined experiences underscore the critical need for integrated, culturally sensitive strategies combining genetic testing, enhanced surveillance, and family-based management to improve outcomes for individuals and families affected by hereditary CRC. Future efforts should focus on addressing disparities in access to care and expanding research to improve understanding and management of this complex disease.
Familial adenomatous polyposis (FAP) is an inherited condition that predisposes individuals to colorectal cancer without preventive treatment. Surgical management typically involves restorative proctocolectomy with an il...Familial adenomatous polyposis (FAP) is an inherited condition that predisposes individuals to colorectal cancer without preventive treatment. Surgical management typically involves restorative proctocolectomy with an ileal pouch anal anastomosis or colectomy with ileorectal anastomosis. Complete removal of the large intestine and rectum with a permanent stoma may also be required in selected cases. This narrative review highlights decision-making in FAP regarding the timing, extent, and modality of large bowel surgery. Key considerations include the extent of polyps, cancer risk in the remaining rectum, and associated extra-colonic manifestations like desmoid disease. The timing of surgery and the extent of bowel removal are critical factors requiring a personalized approach that considers patient preferences and clinical factors. Regardless of the chosen strategy, continued surveillance is essential to monitor disease progression.
Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predispo...Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.
Watanabe T, Kimura K, Kakimoto M
… +11 more, Hiraoka Y, Matsukawa M, Nagahashi H, Horiguchi S, Toshima M, Tomozawa C, Aitani M, Kuwata T, Yoshida T, Hirata M, Tanabe N
This study aimed to develop and validate a Multidimensional Impact of Cancer Risk Assessment questionnaire-Japanese version (MICRA-J) as an assessment of the psychosocial impact of genetic testing. The MICRA was translat...This study aimed to develop and validate a Multidimensional Impact of Cancer Risk Assessment questionnaire-Japanese version (MICRA-J) as an assessment of the psychosocial impact of genetic testing. The MICRA was translated into Japanese using standardized translation procedures. The reliability and validity of the MICRA-J were evaluated in individuals who underwent BRCA1/2 testing for hereditary breast and ovarian cancer diagnosis. The 72 respondents included patients with BRCA1/2 pathogenic variants (n = 20), BRCA1/2 negative (n = 35), variants of uncertain significance (VUS, n = 6), participants with cascade testing positive (n = 7), and participants with cascade testing negative (n = 4). Total MICRA-J scores were positively correlated with Hospital Anxiety and Depression Scale (HADS) scores and negatively correlated with the 36-item short-form version 2 acute (SF-36v2 acute) scores (P < 0.05). The MICRA-J showed good internal consistency coefficients (α > 0.70). Furthermore, high test-retest correlations were obtained when the 64 participants responded to the MICRA-J twice within a short period (Pearson's correlation coefficient = 0.85). The MICRA-J Total score was higher in the groups with BRCA1/2 pathogenic variant carriers than in the BRCA1/2 negative group, whereas the HADS and SF36v2 acute did not differ significantly. These results suggest that the reliability and validity of the MICRA-J have been established. The MICRA-J, similar to the MICRA in other languages, is considered a useful tool to specifically measure the psychosocial impact of genetic testing.
SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SM...SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SMARCB1 is also an important tumour suppressor gene and somatic SMARCB1 pathogenic variants (PVs) have been detected in ~ 5% of all human cancers. Additionally, germline SMARCB1 PVs have been identified in patients with conditions as clinically diverse as Rhabdoid Tumour Predisposition Syndrome type 1 (RTPS1), schwannomatosis and neurodevelopmental disorders such as Coffin-Siris syndrome (CSS). RTPS1 is characterized by the occurrence of highly malignant atypical teratoid rhabdoid tumours (AT/RT) affecting mostly infants, whereas SMARCB1-related schwannomatosis is generally diagnosed after the age of 30 and is characterized by benign schwannomas. Patients with germline SMARCB1 PVs and neurodevelopmental disorders do not usually develop SMARCB1-deficient tumours but instead exhibit severe intellectual disability and congenital malformations. It is intriguing how germline SMARCB1 PVs can be responsible for these very different pathologies. However, a network of different factors has emerged that play important roles in this context. Thus, the tumour phenotype associated with germline SMARCB1 PVs is determined by the nature and location of the SMARCB1 mutation and the timing of SMARCB1 inactivation in specific progenitor cells. Biallelic complete loss of SMARCB1 function during a narrow time window of early embryonic development in neural crest cells is essential for AT/RT development. By contrast, hypomorphic SMARCB1 PVs during later developmental stages affecting more differentiated Schwann cell precursors give rise to schwannomas. However, the loss of the wild-type SMARCB1 allele is insufficient for schwannoma growth which appears to be dependent upon concomitant somatic NF2 PVs in patients with SMARCB1-related schwannomatosis according to the four-hit/three-step model of tumorigenesis. In patients with neurodevelopmental disorders such as CSS, germline PVs would appear to cluster within the C-terminal SMARCB1 domain, interfering with the nucleosomal interactions of SMARCB1 but not with its tumour suppressor activity.
Tumor molecular profiling (TMP) with germline genetic testing (GGT) is becoming standard practice in pediatric cancer care. Yet, little is known about parents' understanding of these practices, or testing's psychosocial...Tumor molecular profiling (TMP) with germline genetic testing (GGT) is becoming standard practice in pediatric cancer care. Yet, little is known about parents' understanding of these practices, or testing's psychosocial risks and benefits. This study characterized parental knowledge, attitudes, and beliefs about TMP and GGT. A cross-sectional, mixed-methods study was conducted among N = 75 parents of children with cancer. Parents completed a survey on cancer-related knowledge, attitudes toward GGT, psychological stress, communication, and decision-making. A subset (N = 31, 41%) then completed interviews about TMP and GGT that were content-coded and interpreted in light of survey findings. Correlative analyses indicated that parents' greater understanding of cancer and genetics was associated with favorable attitudes toward GGT (r = 0.34), preferences for more information about GGT results (r = 0.56) and reduced decisional regret about GGT (r = -0.61). Families who communicated less openly held more favorable views on GGT (r = -0.38) and preferred more information about GGT (r = -0.39), but had children who were more anxious (r = -0.36). Parents who were more anxious (r = 0.40) and who favored GGT (r = 0.41) also had children who were more anxious (all p's < 0.05). Thematically, most parents recalled their children's test results (94%), but recollection of testing type was suboptimal (58% for TMP, 61% for GGT). Nearly 70% believed it would be helpful to speak to other families for psychosocial support; additional potential resources included healthcare providers (31%) and websites (23%). When children with cancer undergo TMP and/or GGT, their parents would benefit psychoeducational resources to improve outcomes.