Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

A systematic review and meta-analysis of the impacts of germline pharmacogenomics on severe toxicity and symptom burden in adult patients with cancer.

The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.

Establishment, characterization, and genetic profiling of patient-derived osteosarcoma cells from a patient with retinoblastoma.

Osteosarcoma is the most common malignant bone cancer in pediatric patients. Patients who respond poorly to chemotherapy experience worse clinical outcomes with a high mortality rate. The major challenge is the lack of effective drugs for these patients. To introduce new drugs for clinical approval, preclinical studies based on in vitro models must demonstrate the potency of the tested drugs, enabling the drugs to enter phase 1 clinical trials. Patient-derived cell culture is a promising testing platform for in vitro studies, as they more accurately recapitulate cancer states and genetic profiles compared to cell lines. In the present study, we established patient-derived osteosarcoma cells (PDC) from a patient who had previously been diagnosed with retinoblastoma. We identified a new variant of a germline mutation in the RB1 gene in the tissue of the patient. The biological effects of this PDC were studied to observe whether the cryopreserved PDC retained a feature of fresh PDC. The cryopreserved PDC preserved the key biological effects, including cell growth, invasive capability, migration, and mineralization, that define the conserved phenotypes compared to fresh PDC. From whole genome sequencing analysis of osteosarcoma tissue and patient-derived cells, we found that cryopreserved PDC was a minor population in the origin tissue and was selectively grown under the culture conditions. The cryopreserved PDC has a high resistance to conventional chemotherapy. This study demonstrated that the established cryopreserved PDC has the aggressive characteristics of osteosarcoma, in particular the chemoresistance phenotype that might be used for further investigation in the chemoresistant mechanism of osteosarcoma. In conclusion, the approach we applied for primary cell culture might be a promising method to generate in vitro models for functional testing of osteosarcoma.

Genetic changes in the FH gene cause vagal paraganglioma.

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Assessment of BRCA1 and BRCA2 Germline Variant Data From Patients With Breast Cancer in a Real-World Data Registry.

PURPOSE: The emergence of large real-world clinical databases and tools to mine electronic medical records has allowed for an unprecedented look at large data sets with clinical and epidemiologic correlates. In clinical cancer genetics, real-world databases allow for the investigation of prevalence and effectiveness of prevention strategies and targeted treatments and for the identification of barriers to better outcomes. However, real-world data sets have inherent biases and problems (eg, selection bias, incomplete data, measurement error) that may hamper adequate analysis and affect statistical power. METHODS: Here, we leverage a real-world clinical data set from a large health network for patients with breast cancer tested for variants in BRCA1 and BRCA2 (N = 12,423). We conducted data cleaning and harmonization, cross-referenced with publicly available databases, performed variant reassessment and functional assays, and used functional data to inform a variant's clinical significance applying American College of Medical Geneticists and the Association of Molecular Pathology guidelines. RESULTS: In the cohort, White and Black patients were over-represented, whereas non-White Hispanic and Asian patients were under-represented. Incorrect or missing variant designations were the most significant contributor to data loss. While manual curation corrected many incorrect designations, a sizable fraction of patient carriers remained with incorrect or missing variant designations. Despite the large number of patients with clinical significance not reported, original reported clinical significance assessments were accurate. Reassessment of variants in which clinical significance was not reported led to a marked improvement in data quality. CONCLUSION: We identify the most common issues with BRCA1 and BRCA2 testing data entry and suggest approaches to minimize data loss and keep interpretation of clinical significance of variants up to date.

On the Hunt for the Missed Genetic Causes of Multiple Primary Tumors.

Improved cancer screening and treatment programs have led to an increased survivorship of patients with cancer, but consequently also to the rise in number of individuals with multiple primary tumors (MPT). Germline testing is the first approach investigating the cause of MPT, as a positive result provides a diagnosis and proper clinical management to the affected individual and their family. Negative or inconclusive genetic results could suggest non-genetic causes, but are negative genetic results truly negative? Herein, we discuss the potential sources of missed genetic causes and highlight the trove of knowledge MPT can provide. See related article by Borja et al., p. 209.

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype.

Importance: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. Objectives: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. Design, Setting, and Participants: This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Main Outcomes and Measures: Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Results: Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). Conclusions and Relevance: In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil. METHODS: A cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes. RESULTS: The prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time. CONCLUSION: One in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata.

Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Familial rare EGFR-mutant lung cancer syndrome: Review of literature and description of R776H family.

BACKGROUND: Interest in hereditary lung cancer is increasing, in particular germline mutations in the Epidermal Growth Factor Receptor (EGFR) gene. We review the current literature on this topic, discuss risk of developing lung cancer, treatment and screening options and describe a family of 3 sisters with lung cancer and their unaffected mother all with a rare EGFR germline mutation (EGFR p.R776H). METHODS: We searched PubMed, Medline, Embase, the Cochrane Library, Google Scholar and scanned reference lists of articles. Search terms included "EGFR germline" and "familial lung cancer" or "EGFR familial lung cancer". We also describe our experience of managing a family with rare germline EGFR mutant lung cancer. RESULTS: Although the numbers are small, the described cases in the literature show several similarities. The patients are younger and usually have no or light smoking history. 50% of the patients were treated with a tyrosine kinase inhibitor (TKIs) with OS over six months. CONCLUSION: Although rare, germline p.R776H EGFR lung cancer mutations are over-represented in light or never smoking female patients who often also possess an additional somatic EGFR mutation. Treatment with TKIs appears suitable but further research is needed into the appropriate screening regime for unaffected carriers or light/never smokers.

Predisposing deleterious variants in the cancer-associated human kinases in the global populations.

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.

Population-based BRCA germline mutation screening in the Han Chinese identifies individuals at risk of BRCA mutation-related cancer: experience from a clinical diagnostic center from greater Shanghai area.

BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Germline genetic regulation of the colorectal tumor immune microenvironment.

OBJECTIVE: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC). METHODS: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication. RESULTS: We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10- 8, with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A (P = 0.012) in healthy colon mucosa. CONCLUSIONS: Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms.

Tumor analysis of MMR genes in Lynch-like syndrome: Challenges associated with results interpretation.

BACKGROUND: Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch-like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in a variable range of LLS-associated tumors. Moreover, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated with the implementation of tumoral MMR gene testing in routine workflows. METHODS: Here, we present the clinical characterization of 229 LLS patients. MMR gene testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥5% and ≥10%). RESULTS AND DISCUSSION: More biallelic somatic events were identified at VAF ≥ 5% than ≥10% (35.9% vs. 25.6%), although the rate of nonconcordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

The Genetic Paradigm of Hereditary Breast and Ovarian Cancer (HBOC) in the Afro-Caribbean Population.

Differences in tumor biology and genetic predisposition have been suggested as factors influencing overall survival and increased mortality in Black breast and ovarian cancer patients. Therefore, it is key to evaluate genetic susceptibilities in Afro-Caribbean patients because the black population in the US is not homogeneous. Identifying a high incidence of hereditary breast and ovarian cancer (HBOC) in Afro-Caribbean countries can lead to understanding the pattern of inherited traits in US-Caribbean immigrants and their subsequent generations. The paucity of projects studying the genetic landscape in these populations makes it difficult to design studies aimed at optimizing screening and prophylaxis strategies, which in turn, improve survival and mortality rates. This scoping review identifies and categorizes current research on the genetic paradigm of HBOC in the Afro-Caribbean population. We performed an evaluation of the evidence and generated a summary of findings according to preferred reporting items for systematic review and meta-analysis (PRISMA) Extension for Scoping Reviews guidelines. We included articles that assessed the incidence and prevalence of pathologic germline mutations and experience/barriers for genetic testing in Afro-Caribbean Countries and US-Caribbean patients. Our results highlight countries where genetic landscapes remain severely understudied and support recommending multigene testing in Caribbean-born patients. They highlight a need for further research on the genetic paradigm of HBOC in the Afro-Caribbean population to improve genetic testing/counseling and the subsequent adoption of early detection and risk reduction strategies.