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Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

ABSTRACT: Inherited pathogenic variants in genes that confer moderate to high risk of breast cancer may explain up to 50% of familial breast cancer. This study aimed at identifying inherited pathogenic variants in breast cancer cases from Puerto Rico that were not linked to BRCA1 or BRCA2. Forty-eight breast cancer patients that met the clinical criteria for BRCA testing but had received a negative BRCA1/2 result were recruited. Fifty-three genes previously implicated in hereditary cancer predisposition were captured using the BROCA Agilent cancer risk panel followed by massively parallel sequencing. Missense variants of uncertain clinical significance in CHEK2 were evaluated using an in vitro kinase assays to determine their impact on function. Pathogenic variants were identified in CHEK2, MUTYH, and RAD51B in four breast cancer patients, which represented 8.3% of the cohort. We identified three rare missense variants of uncertain significance in CHEK2 and two variants (p.Pro484Leu and p.Glu239Lys) showed markedly decreased kinase activity in vitro comparable to a known pathogenic variant. Interestingly, the local ancestry at the RAD51B locus in the carrier of p.Arg47* was predicted to be of African origin. In this cohort, 12.5% of the BRCA-negative breast cancer patients were found to carry a known pathogenic variant or a variant affecting protein activity. This study reveals an unmet clinical need of genetic testing that could benefit a significant proportion of at-risk Latinas. It also highlights the complexity of Hispanic populations as pathogenic factors may originate from any of the ancestral populations that make up their genetic backgrounds.

SUBMITTER: Dutil J

PROVIDER: S-EPMC6882826 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundHospitalization of patients during outbreaks of chikungunya virus has been reported to be uncommon (0.5-8.7%), but more frequent among infants and the elderly. CHIKV was first detected in Puerto Rico in May 2014. We enrolled patients with acute febrile illness (AFI) presenting to two hospital emergency departments in Puerto Rico and tested them for CHIKV infection to describe the frequency of detection of CHIKV-infected patients, identify risk factors for hospitalization, and describe patients with severe manifestations.Methodology/principal findingsSerum specimens were collected from patients with AFI and tested by rRT-PCR. During May-December 2014, a total of 3,035 patients were enrolled, and 1,469 (48.4%) had CHIKV infection. A total of 157 (10.7%) CHIKV-infected patients were hospitalized, six (0.4%) were admitted to the intensive care unit, and two died (0.1%). Common symptoms among all CHIKV-infected patients were arthralgia (82.6%), lethargy (80.6%), and myalgia (80.5%). Compared to patients aged 1-69 years (7.3%), infant (67.2%) and elderly (17.3%) patients were nine and two times more likely to be hospitalized, respectively (relative risk [RR] and 95% confidence interval [CI] = 9.16 [7.05-11.90] and 2.36 [1.54-3.62]). Multiple symptoms of AFI were associated with decreased risk of hospitalization, including arthralgia (RR = 0.31 [0.23-0.41]) and myalgia (RR = 0.29 [0.22-0.39]). Respiratory symptoms were associated with increased risk of hospitalization, including rhinorrhea (RR = 1.68 [1.24-2.27) and cough (RR = 1.77 [1.31-2.39]). Manifestations present among <5% of patients but associated with patient hospitalization included cyanosis (RR = 2.20 [1.17-4.12) and seizures (RR = 3.23 [1.80-5.81).DiscussionAmong this cohort of CHIKV-infected patients, hospitalization was uncommon, admission to the ICU was infrequent, and death was rare. Risk of hospitalization was higher in patients with symptoms of respiratory illness and other manifestations that may not have been the result of CHIKV infection.

Project description:The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited. The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored. We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes. We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04) than Germline-others group. Meanwhile, Germline-others group and Others group are very similar (P>0.05). The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups. By investigating all breast and ovarian cancer-related genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening. Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.

Project description:Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets. Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan-Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression. Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47-69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity. Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

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Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

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