Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing

Lu, Hsiao-Mei; Li, Shuwei; Black, Mary Helen; Lee, Shela; Hoiness, Robert; Wu, Sitao; Mu, Wenbo; Huether, Robert; Chen, Jefferey; Sridhar, Srijani; Tian, Yuan; McFarland, Rachel; Dolinsky, Jill S.; Davis, Brigette Tippin; Mexal, Sharon; Dunlop, Charles; Elliott, Aaron

doi:10.1001/jamaoncol.2018.2956

Cited by 160 publications

(172 citation statements)

References 48 publications

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“…Four different truncating ATM mutations were seen in six cases (1% of non‐ BRCA cases). There is evidence that ATM protein‐truncating mutations are associated with a twofold to threefold increase in breast cancer risk . A meta‐analysis of 26 studies (including 4,076 cases and 2,389 controls) performed in 2009 reported an OR of 2.1 (95% CI 1.03–4.21) for breast cancer for carriers of truncating ATM mutations .…”

Section: Discussionmentioning

confidence: 99%

The spectrum of mutations predisposing to familial breast cancer in Poland

Cybulski

Kluźniak

Huzarski

et al. 2019

Intl Journal of Cancer

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To optimize genetic testing, it is necessary to establish the spectrum of breast cancer‐predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non‐BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2‐positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non‐BRCA‐positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.

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Section: Discussionmentioning

confidence: 99%

The spectrum of mutations predisposing to familial breast cancer in Poland

Cybulski

Kluźniak

Huzarski

et al. 2019

Intl Journal of Cancer

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“…91 Variants have been associated with ovarian cancer risk (OR = 18.50, 95% CI 2.56-808.1). 92 However, numerous studies have not found germline TP53 variants to be significantly associated with ovarian cancer or to affect risk. 61,93-96…”

Section: Tp53mentioning

confidence: 99%

“…The crucial role of TP53 is exemplified by Li‐Fraumeni syndrome, a disorder with close to 100% cancer incidence by age 70; the median age of ovarian cancer in these patients is 39.5 years . Variants have been associated with ovarian cancer risk (OR = 18.50, 95% CI 2.56‐808.1) . However, numerous studies have not found germline TP53 variants to be significantly associated with ovarian cancer or to affect risk …”

Section: Introductionmentioning

confidence: 99%

Epithelial ovarian cancer risk: A review of the current genetic landscape

et al. 2019

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Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained.This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately. K E Y W O R D SBRCA, genetic risk, homologous recombination, mismatch repair, ovarian cancer, polygenic risk score, SNPs

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“…5,7,11 The missing heritability could be partially attributed to risk-associated rare coding variants (MAF < 0.5%), which typically have large effect sizes, as demonstrated in multiple hereditary breast cancer genes, such as BRCA1, BRCA2, ATM, TP53, CHEK2, PALB2, CDH1, STK11, NF1 and PTEN. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] Two recent case-control association studies conducted in European-ancestry populations discovered many new pathogenic coding variants by sequencing known cancer predisposition genes. 22,23 However, rare coding variants in known breast cancer susceptibility genes and other less well-characterized genes have not been adequately investigated in Asian populations.…”

Section: Introductionmentioning

confidence: 99%

Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

Guo

Long

Chen

et al. 2019

Intl Journal of Cancer

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The missing heritability of breast cancer could be partially attributed to rare variants (MAF < 0.5%). To identify breast cancer‐associated rare coding variants, we conducted whole‐exome sequencing (~50×) in genomic DNA samples obtained from 831 breast cancer cases and 839 controls of Chinese females. Using burden tests for each gene that included rare missense or predicted deleterious variants, we identified 29 genes showing promising associations with breast cancer risk. We replicated the association for two genes, OGDHL and BRCA2, at a Bonferroni‐corrected p < 0.05, by genotyping an independent set of samples from 1,628 breast cancer cases and 1,943 controls. The association for OGDHL was primarily driven by three predicted deleterious variants (p.Val827Met, p.Pro839Leu, p.Phe836Ser; p < 0.01 for all). For BRCA2, we characterized a total of 27 disruptive variants, including 18 nonsense, six frameshift and three splicing variants, whereas they were only detected in cases, but none of the controls. All of these variants were either very rare (AF < 0.1%) or not detected in >4,500 East Asian women from the genome Aggregation database (gnomAD), providing additional support to our findings. Our study revealed a potential novel gene and multiple disruptive variants of BRCA2 for breast cancer risk, which may identify high‐risk women in Chinese populations.

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Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing

Cited by 160 publications

References 48 publications

The spectrum of mutations predisposing to familial breast cancer in Poland

The spectrum of mutations predisposing to familial breast cancer in Poland

Epithelial ovarian cancer risk: A review of the current genetic landscape

Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

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