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1.
Pharmacogenet Genomics ; 31(1): 1-9, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32649577

RESUMO

OBJECTIVES: Based on our previous findings that postmenopausal women with estrone (E1) and estradiol (E2) concentrations at or above 1.3 pg/ml and 0.5 pg/ml, respectively, after 6 months of adjuvant anastrozole therapy had a three-fold risk of recurrence, we aimed to identify a single-nucleotide polymorphism (SNP)-based model that would predict elevated E1 and E2 and then validate it in an independent dataset. PATIENTS AND METHODS: The test set consisted of 322 women from the M3 study and the validation set consisted of 152 patients from MA.27. All patients were treated with adjuvant anastrozole, had on-anastrozole E1 and E2 concentrations and genome-wide genotyping. RESULTS: SNPs were identified from the M3 genome-wide association study. The best model to predict the E1-E2 phenotype with high balanced accuracy was a support vector machine model using clinical factors plus 46 SNPs. We did not have an independent cohort that is similar to the M3 study with clinical, E1-E2 phenotypes and genotype data to test our model. Hence, we chose a nested matched case-control cohort (MA.27 study) for testing. Our E1-E2 model was not validated but we found the MA.27 validation cohort was both clinically and genomically different. CONCLUSIONS: We identified a SNP-based model that had excellent performance characteristics for predicting the phenotype of elevated E1 and E2 in women treated with anastrozole. This model was not validated in an independent dataset but that dataset was clinically and genomically substantially different. The model will need validation in a prospective study.

2.
Nat Genet ; 52(11): 1219-1226, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33106634

RESUMO

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

3.
J Clin Oncol ; : JCO2002151, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33119476

RESUMO

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2. METHODS: Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION: PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

4.
NPJ Breast Cancer ; 6: 53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083532

RESUMO

Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs; n = 132 and n = 127, respectively), mixed mucinous (n = 5 metastatic and n = 14 primary), micropapillary (n = 12 metastatic and n = 8 primary), and metaplastic BCs (n = 6 metastatic and n = 5 primary), and compared metastatic histologic special types of BC to metastatic IDC-NSTs matched according to clinicopathologic characteristics and to primary special type BCs. The genomic profiles of metastatic and primary special types of BC were similar. Important differences, however, were noted: metastatic ILCs harbored a higher frequency of genetic alterations in TP53, ESR1, FAT1, RFWD2, and NF1 than primary ILCs, and in CDH1, PIK3CA, ERBB2, TBX3, NCOR1, and RFWD2 than metastatic IDC-NSTs. Metastatic ILCs displayed a higher mutational burden, and more frequently dominant APOBEC mutational signatures than primary ILCs and matched metastatic IDC-NSTs. ESR1 and NCOR mutations were frequently detected in metastatic mixed mucinous BCs, whereas PIK3CA and TP53 were the most frequently altered genes in metastatic micropapillary and metaplastic BCs, respectively. Taken together, primary and metastatic BCs histologic special types have remarkably similar repertoires of somatic genetic alterations. Metastatic ILCs more frequently harbor APOBEC mutational signatures than primary ILCs and metastatic IDC-NSTs.

5.
Nat Cancer ; 1(4): 382-393, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32864625

RESUMO

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32954205

RESUMO

PURPOSE: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

7.
JCI Insight ; 5(16)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32701512

RESUMO

Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer-free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.

8.
Clin Cancer Res ; 26(13): 3239-3247, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32444418

RESUMO

PURPOSE: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome. EXPERIMENTAL DESIGN: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden. RESULTS: Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum. CONCLUSIONS: Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.

9.
J Clin Oncol ; 38(18): 2080-2106, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32243226

RESUMO

PURPOSE: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS: Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

10.
Public Health Genomics ; 23(1-2): 6-19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191943

RESUMO

INTRODUCTION: Genetic risk modifier testing (GRMT), an emerging form of genetic testing based on common single nucleotide polymorphisms and polygenic risk scores, has the potential to refine estimates of BRCA1/2 mutation carriers' breast cancer risks. However, for women to benefit from GRMT, effective approaches for communicating this novel risk information are needed. OBJECTIVE: To evaluate patient preferences regarding risk communication materials for GRMT. METHODS: We developed four separate presentations (panel of genes, icon array, verbal risk estimate, graphical risk estimate) of hypothetical GRMT results, each using varying risk communication strategies to convey different information elements including number of risk modifier variants present, variant prevalence among BRCA1/2 carriers, and implications and uncertainties of test results for cancer risk. Thirty BRCA1/2 carriers evaluated these materials (randomized to low, moderate, or high breast cancer risk versions). Qualitative and quantitative data were obtained through in-person interviews. RESULTS: Across risk versions, participants preferred the presentation of the graphical risk estimate, often in combination with the verbal risk estimate. Interest in GRMT was high; 76.7% of participants wanted their own GRMT. Participants valued the potential for GRMT to clarify their cancer susceptibility and provide actionable information. Many (65.5%) anticipated that GRMT would make risk management decisions easier. CONCLUSIONS: Women with BRCA1/2 mutations could be highly receptive to GRMT, and the minimal amount of necessary information to be included in result risk communication materials includes graphical and verbal estimates of future cancer risk. Findings will inform clinical translation of GRMT in a manner consistent with patients' preferences.

11.
J Natl Cancer Inst ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32119081

RESUMO

Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer-associated genes is unknown. In a population-based case-control study, we examined the association between RT, variants in ATM, BRCA1/2, or CHEK2*1100delC, and CBC risk. We analyzed 708 cases of women with CBC, and 1,399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985-2000, <55 years of age at diagnosis, and screened for variants in breast cancer-associated genes. Rate ratios and 95% confidence intervals were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (e.g., BRCA1/2 pathogenic variant carriers without RT, RR: 3.52, 95% CI: 1.76-7.01; BRCA1/2 pathogenic variant carriers with RT, RR: 4.46, 95% CI: 2.96-6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT, RR: 0.38, 95% CI: 0.09-1.55; carriers of ATM rare missense variants of uncertain significance with RT, RR: 2.98, 95% CI: 1.31-6.80). Further mechanistic studies will aid clinical decision-making related to RT.

12.
Cancer ; 126(9): 1995-2002, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32012241

RESUMO

BACKGROUND: With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs). METHODS: Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected. RESULTS: Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate-penetrance cancer predisposition gene. Among high-penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer. CONCLUSIONS: The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.

13.
J Clin Oncol ; 38(13): 1398-1408, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922925

RESUMO

PURPOSE: Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or "cascade" of genomic risk information. METHODS: Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size. RESULTS: The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations. CONCLUSION: Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

14.
Hum Mutat ; 41(1): 103-109, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444830

RESUMO

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431_1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK-IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431_1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431_1433dupAAA variant. Our data indicate the FH c.1431_1433dupAAA is not associated with cancer including renal cell carcinoma.

16.
J Clin Oncol ; 38(5): 406-414, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31794323

RESUMO

PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias Urológicas/genética , Hidrolases Anidrido Ácido/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Estudos Prospectivos
17.
J Thorac Oncol ; 15(4): 655-660, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31887429

RESUMO

INTRODUCTION: Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs). METHODS: We analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected. RESULTS: Of 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer. CONCLUSIONS: Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.

18.
Nat Med ; 25(12): 1928-1937, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768066

RESUMO

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Genômica , Neoplasias/sangue , Adulto , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Análise Mutacional de DNA , DNA de Neoplasias/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Neoplasias/patologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-31511843

RESUMO

PURPOSE: Germline CDH1 pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of CDH1 PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for CDH1 variants in the multigene panel testing era. METHODS: Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding CDH1 genetic testing experiences, medical management, and psychosocial adaptation. RESULTS: Discordance existed in interpretations of CDH1 results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers' knowledge and reported less CDH1 knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS. CONCLUSION: Few individuals with CDH1 PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants' CDH1 results, suggesting serious unmet informational needs.

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