Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk

Caswell-Jin, Jennifer L.; Gupta, Tanya; Hall, Evan; Petrovchich, Iva; Mills, Meredith; Kingham, Kerry; Koff, Rachel; Chun, Nicolette M.; Levonian, Peter; Lebensohn, Alexandra; Ford, James M.; Kurian, Allison W.

doi:10.1038/gim.2017.96

Cited by 139 publications

(104 citation statements)

References 21 publications

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“…While BRCA1/2 variant positive individuals had significantly increased risk of HBOC-related cancers, those with uncertain/conflicting variants did not, suggesting that many of these variants are likely to be benign or of low penetrance. These data add to a growing body of literature (19)(20)(21) underscoring the pressing need to further characterize genomic variation across diverse populations.…”

Section: Discussionmentioning

confidence: 77%

“…Understanding of the prevalence and contribution to cancer risk of BRCA1/2 variants in non-European populations has been limited by racial and ethnic disparities in genetic research (14). In addition to reduced uptake of genetic testing in diverse populations (15)(16)(17)(18), there is a higher rate of detection of variants of uncertain significance in non-European populations (19)(20)(21). Here, we evaluated the range of BRCA1/2 variants in a diverse patient population from the BioMe Biobank in New York City, and explored clinical characteristics of individuals harboring expected pathogenic variants in BRCA1/2.…”

Section: Introductionmentioning

confidence: 99%

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Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Abul‐Husn

Soper

Odgis

et al. 2019

Preprint

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Word Count: 340 Manuscript Word Count: 4214Abstract Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant positive individuals in the general population are unaware of their risk, and little is known about the prevalence of pathogenic BRCA1/2 variants in non-European populations.We investigated BRCA1/2 prevalence and impact using exome sequencing and electronic health record (EHR) data from 30,223 adult participants of the BioMe Biobank in New York City. There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. In subpopulations defined by genetic ancestry, the highest prevalence was in individuals of Ashkenazi Jewish (AJ; 1 in 49), Filipino and Southeast Asian (1 in 81), and Non-AJ European (1 in 103) descent. Among 218 variant positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 7 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 25 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar, or that had uncertain or conflicting evidence for pathogenicity. Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion African genetic ancestry and the likelihood of harboring a BRCA1/2 variant with uncertain or conflicting evidence for pathogenicity. Based on EHR and participant questionnaire data, ~28% of variant positive individuals had a personal history, and ~45% a personal or family history of BRCA1/2-associated cancers.Approximately 27% of variant positive individuals had evidence of prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (38%) than those with other pathogenic variants (19%). These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Abul‐Husn

Soper

Odgis

et al. 2019

Preprint

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“…By this time, the long‐term risk of malignancy in patients with psoriasis in Asian population has been scarcely investigated. Since not only the psoriasis‐related gene signatures but also the cancer incidence and cancer molecular pathways differ widely based on the ethnicity, cancer risks in Asian psoriasis could not be directly reflected by results from Caucasian population . Considering relatively lower prevalence of psoriasis in Asian countries (0.3–0.4% prevalence rate) compared to western countries, the results from our large‐scale cohort consisting of more than 1.7 million participants enabled us to assess the significant risk of malignancy in Korean patients with psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Risk of malignancy in patients with psoriasis: a 15‐year nationwide population‐based prospective cohort study in Korea

Lee

Kim

et al. 2019

Acad Dermatol Venereol

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Background The association between psoriasis and risk of malignancy has not been thoroughly evaluated in a large longitudinal cohort of Asian population. Objective To determine the long‐term risk of malignancy in Korean adult patients with psoriasis. Methods We conducted a nationwide population‐based prospective cohort study with a 15‐year observational period. During the baseline period (1997–2000), total 1 773 786 Korean subjects who received health insurance from the National Health Insurance System were enrolled and 5788 subjects were defined as a psoriasis group. The number of new‐onset malignancy was collected during the observational period (2001–2015). Results Patients with psoriasis had a higher adjusted hazard ratio (aHR) for development of overall malignancy [aHR 1.08, 95% confidence interval (CI) 1.00–1.18] and gastric cancer (aHR 1.31, 95% CI 1.08–1.58) compared to controls. The risks of non‐Hodgkin lymphoma and non‐melanoma skin cancer were significantly increased only in patients with psoriasis who received systemic treatments (aHR 2.86, 95% CI 1.07–7.61 and aHR 3.93, 95% CI 1.47–10.47, respectively). Conclusion Psoriasis is associated with long‐term risk for overall malignancy in Koreans, which was primarily driven by the increased risk of gastric cancer.

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“…Rare variant classification and interpretation remain a challenge given the low frequency of observation precluding statistical associations. The identification of ancestry-specific predisposing variants further highlights this challenge in minority groups, where current germline sequencing often results in higher rates of variants of unknown significance (VUSs) [10].…”

Section: Discussionmentioning

confidence: 99%

Ancestry-Specific Predisposing Germline Variants in Cancer

Oak

Cherniack

Mashl

et al. 2020

Preprint

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Background: Cancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry.Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds. Methods:We performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestryspecific predisposing variants and their associated somatic two-hit events and gene expression levels.Results: Recent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184 , 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association of BRCA2 in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4];FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84];FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; and FH splice-site variant carriers showed mis-splicing of FH. Conclusions:While several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestryspecific genetic predisposition to inform personalized diagnosis and screening strategies.

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Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk

Cited by 139 publications

References 21 publications

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Risk of malignancy in patients with psoriasis: a 15‐year nationwide population‐based prospective cohort study in Korea

Ancestry-Specific Predisposing Germline Variants in Cancer

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