Pathogenic Germline Variants in Patients With Metastatic Breast Cancer.
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ABSTRACT:
SUBMITTER: Stuttgen K
PROVIDER: S-EPMC6802240 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Pathogenic Germline Variants in Patients With Metastatic Breast Cancer.
Stuttgen Kelsey K Croessmann Sarah S Fetting John J Stearns Vered V Nunes Raquel R Connolly Roisin M RM Park Ben Ho BH
JAMA oncology 20191001 10
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Project description:ImportanceMetaplastic breast cancer (MpBC) is a rare, heterogeneous disease often associated with inferior outcomes. A growing body of literature describes the clinical and molecular features of MpBC, yet limited data describe the pathogenic germline variants (PGVs) in breast cancer susceptibility genes among affected individuals.ObjectiveTo examine the frequency and types of PGVs in breast cancer genes among patients with MpBC.Design, setting, and participantsThis is a descriptive retrospective cohort study of patients who received a diagnosis of MpBC at the University of Pennsylvania between January 2010 and May 2023. Electronic medical records were reviewed for demographic, clinicopathologic, and germline genetic testing information. Germline variant status was independently confirmed by a licensed genetic counselor and a physician with expertise in genetics. MpBC diagnosis and subtype were confirmed by a breast pathologist. Participants were identified via query of an institutional pathology database for reports signed between January 2010 and May 2023 including the term metaplastic. Among 320 initially obtained reports, 272 individuals had confirmed MpBC and were included in the study.ExposureGermline genetic testing to investigate the presence of PGVs in breast cancer susceptibility genes.Main outcomes and measuresThe primary outcome measurement was the prevalence of PGVs in breast cancer susceptibility genes among participants. The hypothesis that individuals with MpBC have an enrichment of PGVs in genes associated with inherited breast cancer risk was formulated before data collection.ResultsThe total sample size was 272 women, and the median age at diagnosis was 58 years (range, 20-102 years); all were biological female patients; 143 of 272 (52.6%) had documentation of germline genetic testing; and participants with testing were significantly younger than those without (median age, 53 years [range, 20-79 years] vs 63 years [range, 29-102 years]; P < .001). Of the 143 patients, 24 (16.8%) had a PGV in a breast cancer susceptibility gene (BRCA1, n = 17; BRCA2, n = 5; PALB2, n = 1; CHEK2, n = 1). Patients with PGV-associated MpBC received a diagnosis at a younger age than those with sporadic disease, but there were no significant differences in hormone receptor positivity, ERBB2 status, or metaplastic subtype.Conclusions and relevanceIn this cohort study of patients with MpBC, a substantial proportion of clinically tested patients had a PGV in a breast cancer susceptibility gene, most commonly BRCA1. Germline testing was high yield in patients with MpBC, many of whom would be included in current germline testing eligibility criteria.
| S-EPMC11836754 | biostudies-literature
Project description:BackgroundCancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung.MethodsExome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case-control association analyses were performed.ResultsAltogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations.ConclusionsWe have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.
| S-EPMC10353088 | biostudies-literature
Project description:BackgroundFew studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC).MethodsThe frequency of pathogenic and likely pathogenic (P/LP) variants in clinically actionable genes (BRCA1, BRCA2, PTEN, TP53, CHEK2, CDH1, ATM, PALB2, NBN, and NF1) was compared between women with a primary breast cancer (PBC) and SBC who underwent multigene panel testing at a single diagnostic testing laboratory. Race- and ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes were used to test for associations with SBC. All statistical tests were 2-sided.ResultsThe study was comprised of 75 550 women with PBC and 7728 with SBC. Median time between breast cancers for SBC was 11 (interquartile range = 6-17) years. Restricting to women tested for all actionable genes (n = 60 310), there were 4231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared with 652 (11.1%) women with SBC (P< .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% confidence interval [CI] = 1.30 to 1.60) times as likely to have SBC than noncarriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (95% CI = 1.36 to 2.56) and 1.66 (9% CI = 1.02 to 2.58) times as likely to be associated with SBC, respectively (P < .001 and P = .03).ConclusionWomen with P/LP variants in breast cancer predisposition genes are more likely to have SBC than noncarriers. Prospective studies are needed confirm these findings.
| S-EPMC7771422 | biostudies-literature
Project description:Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ?80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.
| S-EPMC6172276 | biostudies-literature
Project description:The prevalence and clinical relevance of pathogenic germline variants in MMR genes have not been investigated in large series of breast cancers. In this study, we screened the germline variants in MMR genes in 8085 consecutive Chinese breast cancer patients, and investigated the MMR/PD-L1 protein expression and tumor mutation burden (TMB) of breast tumors from MMR variant carriers. We found that 15 of 8085 patients (0.19%) carried a pathogenic germline variant in MMR genes. Compared with non-carriers, MMR variant carriers might have worse recurrence-free survival (unadjusted hazard ratios [HR] = 2.70, 95% CI: 1.12-6.49, P = 0.027) and distant recurrence-free survival (unadjusted HR = 3.24, 95% CI: 1.45-7.22, P = 0.004). More importantly, some of the breast cancers from MMR carriers displayed MMR protein loss (5/13), TMB-high (2/10), and PD-L1 positive expression (9/13). This study showed that MMR variant carriers were rare in breast cancer. They might have worse survival and part of them might benefit from immunotherapy.
| S-EPMC9023502 | biostudies-literature
Project description:PurposeGermline genetic testing (GGT) is now recommended for all patients diagnosed with ovarian or pancreatic cancer and for a large proportion of patients based solely on a diagnosis of colorectal or breast cancer. However, GGT is not yet recommended for all patients diagnosed with lung cancer (LC), primarily because of a lack of evidence that supports a significant frequency of identifying pathogenic germline variants (PGVs) in these patients. This study characterizes GGT results in a cohort of patients with LC.MethodsWe reviewed deidentified data for 7,788 patients with GGT (2015-2022). PGV frequencies were compared to a control cohort of unaffected individuals. GGT results were stratified by genomic ancestry, history of cancer, and PGV clinical actionability per current guidelines.ResultsOf all patients with LC, 14.9% (1,161/7,788) had PGVs. The rate was similar when restricted to patients with no cancer family history (FH) or personal history (PH) of other cancers (14.3%). PGVs were significantly enriched in BRCA2, ATM, CHEK2, BRCA1, and mismatch repair genes compared with controls. Patients of European (EUR) genomic ancestry had the highest PGV rate (18%) and variants of uncertain significance were significantly higher in patients of non-EUR genomic ancestry. Of the PGVs identified, 61.3% were in DNA damage repair (DDR) genes and 95% were clinically actionable.ConclusionThis retrospective study shows a LC diagnosis identifies patients with a significant likelihood of having a cancer-predisposing PGV across genomic ancestries. Enrichment of PGVs in DDR genes suggests that these PGVs may contribute to LC cancer predisposition. The frequency of PGVs among patients with LC did not differ significantly according to FH or PH of other cancers.
| S-EPMC10681406 | biostudies-literature
Project description:Metaplastic breast cancer (MpBC) is a rare, aggressive breast cancer (BC) histotype. Scarce information is available about MpBC genetic predisposition. Previous studies, mainly consisting of case reports, retrospective reviews and others on target therapies, pointed to a possible involvement of the BRCA1 gene in increasing MpBC risk, without ever confirming it. In this study, we retrospectively reviewed all BC patients counseled at our Institute for genetic testing of at least BRCA1 or BRCA2 (BRCA) genes and we found that 23 (23/5226 = 0.4%) were affected by MpBC. About 65% (15/23) of MpBC patients harbored a germline pathogenic variant (PV): 13 in BRCA1 (86.7%), including two patients who received genetic testing for known familial PV, one in TP53 (6.7%), and one in MLH1 (6.7%). We observed a statistically different frequency of MpBC in patients who carried a PV in the BRCA genes (13/1114 = 1.2%) vs. all other BC patients (10/4112 = 0.2%) (p = 0.0002). BRCA carriers proved to have an increased risk of developing MpBC compared to all other BC patients who were tested for BRCA genes (OR = 4.47; 95% CI: 1.95-10.23). Notably, MpBCs were diagnosed in 2.1% (13/610) of BRCA1 carriers. No MpBCs were observed in BRCA2 carriers (0/498 = 0%), revealing a statistically significant difference between the prevalence of MpBCs in BRCA1 and BRCA2 carriers (p = 0.0015). Our results confirmed that BRCA1 is involved in MpBC predisposition. Further studies on unselected patients are needed to elucidate the authentic role of BRCA1 and to explore the possible implication of other genes in MpBC predisposition.
| S-EPMC10620155 | biostudies-literature
Project description:Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.
| S-EPMC7089973 | biostudies-literature
Project description:BackgroundRacial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry-based variations in germline pathogenic variants (gPVs) is unknown.MethodsGermline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor-normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self-reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry.ResultsAmong 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self-reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non-Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p = .009], with similar findings by genetic ancestry (p < .001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22-0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18-0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11-2.34) compared with patients of non-Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability-high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n = 114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%).ConclusionsIn those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention.Plain language summaryBlack women with endometrial cancer do worse than White women, and there are many reasons for this disparity. Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups. Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse.
| S-EPMC10922155 | biostudies-literature
Project description:ImportanceNeuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear.ObjectiveTo define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients.Design setting and participantsGermline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival.Main outcomes and measuresRare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival.ResultsWe observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01).Conclusions and relevanceNeuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.
| S-EPMC9901064 | biostudies-literature