Expansion of Cancer Risk Profile for <i>BRCA1</i> and <i>BRCA2</i> Pathogenic Variants

Momozawa, Yukihide; Sasai, Rumi; Usui, Yoshiaki; Shiraishi, Kouya; Iwasaki, Yusuke; Taniyama, Yukari; Parsons, Michael T.; Mizukami, Keijiro; Sekine, Yuya; Hirata, Makoto; Kamatani, Yoichiro; Endo, Mareyuki; Inai, Chihiro; Takata, Shozo; Ito, Hidemi; Kohno, Takashi; Matsuda, Koichi; Nakamura, Seigo; Sugano, Kokichi; Yoshida, Teruhiko; Nakagawa, Hidewaki; Matsuo, Keitaro; Murakami, Yoshinori; Spurdle, Amanda B.; Kubo, Michiaki

doi:10.1001/jamaoncol.2022.0476

Cited by 103 publications

(88 citation statements)

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“…Pathogenic variants in BRCA1/2 have been found to be associated with risks of multiple primary cancers, including pancreatic and stomach cancers (70). Pathogenic variants in BRCA1/2 are also associated with ovarian cancer risk (71,72), as are pathogenic variants in PALB2 (73), RAD51C (74,75), and RAD51D (75,76). Such observations may explain the elevated ovarian SPC risks found in this review, particularly among younger BC survivors (77,78).…”

Section: Discussionmentioning

confidence: 99%

Risks of Second Non-Breast Primaries Following Breast Cancer in Women: A Systematic Review and Meta-Analysis

Allen

Hassan

Sofianopoulou

et al. 2022

Preprint

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BackgroundSecond primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. MethodsWe conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse-variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale. ResultsOne prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95%CI: 1.14-1.36, I2: 99%). This varied by age: the estimate was 1.59 (95%CI: 1.36-1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95%CI: 1.01-1.36, p for difference: < 0.001). SPC risks were also significantly higher when based on Asian, rather than European, registries (Asia - SIR: 1.47, 95%CI: 1.29-1.67. Europe - SIR: 1.16, 95%CI: 1.04-1.28). There were significantly increased risks of second thyroid (SIR: 1.89, 95%CI: 1.49-2.38), uterus (SIR: 1.84, 95%CI: 1.53-2.23), ovary (SIR: 1.53, 95%CI: 1.35-1.73), kidney (SIR: 1.43, 95%CI: 1.17-1.73), oesophagus (SIR: 1.39, 95%CI: 1.26-1.55), skin (melanoma) (SIR: 1.34, 95%CI: 1.18-1.52), blood (leukaemia) (SIR: 1.30, 95%CI: 1.17-1.45), lung (SIR: 1.25, 95%CI: 1.03-1.51), stomach (SIR: 1.23, 95%CI: 1.12-1.36) and bladder (SIR: 1.15, 95%CI: 1.05-1.26) primaries. ConclusionsBreast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions could inform clinical management decisions following breast cancer.

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Section: Discussionmentioning

confidence: 99%

Risks of Second Non-Breast Primaries Following Breast Cancer in Women: A Systematic Review and Meta-Analysis

Allen

Hassan

Sofianopoulou

et al. 2022

Preprint

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“…This is because, unlike BRCA1/2 , there is still substantial debate as to whether the degree of risk of EOC in individuals with GPVs in these genes is sufficiently higher than that in the general population to warrant consideration of RRSO [ 30 ]. The unreliability of risk estimates for these genes is primarily attributed to the following factors: the GPV prevalence of candidate genes is generally low; individual ovarian cancer studies typically involve fewer cases than breast cancer studies; and most previous analyses lack a comparable control group, which hinders the interpretation of results [ 48 , 49 ].…”

Section: Predisposition Genes Included In This Studymentioning

confidence: 99%

“…Another population-based cohort study reported that the prevalence of BRIP1 GPVs was 0.92–1.36% [ 18 , 71 ]. A larger meta-analysis using approximately 29,400 EOC cases from 63 studies and approximately 116,000 controls from the gnomAD database reported that the prevalence of BRIP1 GPVs in patients with EOC was 0.8891% (200/22,494 cases) and that BRIP1 was significantly associated with EOC (OR = 4.94, 95%CI = 4.07–6.00) [ 49 ]. The NCCN clinical practice guidelines in oncology estimate that the absolute lifetime risk of EOC for individuals with BRIP1 GPVs is >10% [ 46 ].…”

Section: Brip1 (Brca1 Interacting Helicase 1) Genementioning

confidence: 99%

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

Abe

Imoto

Ueki

et al. 2022

IJMS

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Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes.

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“…26 Another study found that in Japanese with pathogenic variants (PVs) of the BRCA2 gene, the accumulative risk of developing PCa was 24.5% by age 85 years, suggesting relative lower risk of PCa incidence related to BRCA mutation in Japanese, compared with Caucasian. 27…”

Section: Hrr Genes and Pca Riskmentioning

confidence: 99%

Role of Olaparib in the Management of Metastatic Castration-Resistant Prostate Cancer: A Japanese Clinician’s Perspective

Matsumoto¹,

Shiota²,

Blas³

et al. 2022

CMAR

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Several studies have identified various targetable genomic alterations in prostate cancer, which accumulate during carcinogenesis and cancer progression. Genomic alterations in genes involved in DNA damage repair by homologous recombination repair may predict increased sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. The Phase 3 PROfound trial has shown that treatment with the PARP inhibitor olaparib was associated with an improved radiographic progression-free survival and overall survival among patients with homologous recombination repair-deficient metastatic castration-resistant prostate cancer (mCRPC) after the treatment with androgen receptor targeting therapy, especially in men with BRCA1 or BRCA2 mutation. In Japan, olaparib was approved in December 2020 for the treatment of mCRPC with BRCA1 or BRCA2 mutation. In addition, genetic tests to detect BRCA1 or BRCA2 mutation to select patients who are likely to benefit from olaparib were also approved. This review summarizes the status of olaparib treatment for mCRPC, focusing on the situation in Japan.

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Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants

Cited by 103 publications

References 50 publications

Risks of Second Non-Breast Primaries Following Breast Cancer in Women: A Systematic Review and Meta-Analysis

Risks of Second Non-Breast Primaries Following Breast Cancer in Women: A Systematic Review and Meta-Analysis

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

Role of Olaparib in the Management of Metastatic Castration-Resistant Prostate Cancer: A Japanese Clinician’s Perspective

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