RESUMO
PURPOSE: Whether germline multigene panel testing (MGPT) should be performed in all individuals with colorectal cancer (CRC) remains uncertain. Therefore, we aimed to determine the yield and potential clinical impact of MGPT across a large, diverse CRC cohort. METHODS: This was a retrospective cohort study of adults with CRC who underwent MGPT of > 10 genes at a commercial laboratory between March 2015 and May 2021. All data were prospectively collected through a single commercial laboratory and retrospectively analyzed. RESULTS: A total of 34,244 individuals with a history of CRC underwent germline MPGT and were included in the analysis. This cohort was predominantly female (60.7%), White (70.6%), and age 50 years or older (68.9%), with 35.5% also reporting a noncolorectal malignancy. At least one pathogenic/likely pathogenic germline variant (PGV) was found in 4,864 (14.2%), with 3,111 (9.1%) having a PGV associated with increased CRC/polyposis risk and 1,048 (3.1%) having an otherwise clinically actionable PGV. Larger gene panels were not clearly associated with higher yield of clinically actionable PGVs. PGVs were more prevalent in individuals of Ashkenazi Jewish descent (P < .001) and Hispanic ethnicity (P < .001). Across all ages, panel sizes, and races/ethnicities, the rate of clinically actionable PGVs on MGPT was 7.9% or greater. A variant of uncertain significance was identified in 13,094 individuals (38.2%). Identification of a variant of uncertain significance associated with panel size (P < .001) and was lower in individuals of Ashkenazi Jewish descent (P < .001), but higher in Black, Asian, and Hispanic individuals (P < .001). CONCLUSION: To our knowledge, this is the largest study to date examining MGPT in CRC, demonstrating high rates of clinically actionable variants detected across all age groups, panel sizes, and racial/ethnic groups. This work supports consideration of broadening germline genetic testing criteria for individuals with CRC.
Assuntos
Neoplasias Colorretais , Testes Genéticos , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Neoplasias Colorretais/diagnóstico , Povo Asiático , EtnicidadeRESUMO
PURPOSE: To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States. METHODS: In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately. RESULTS: Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10-9, B v C P < 2.2×10-16). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%). CONCLUSION: This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.
Assuntos
Neoplasias Ovarianas , Neoplasias da Mama , Carcinoma Epitelial do Ovário , Estudos Transversais , Feminino , Células Germinativas , Hispânico ou Latino/genética , Humanos , América Latina/epidemiologia , Masculino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Prevalência , Estados Unidos/epidemiologiaRESUMO
Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management. MATERIALS AND METHODS: A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory. RESULTS: In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2). CONCLUSION: P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.