Prevalence of nonfounder <i>BRCA1/2</i> mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

Frey, Melissa K.; Kopparam, Rohini; Zhou, Zhen; Fields, Jessica; Buskwofie, A.; Carlson, Ann D.; Caputo, Thomas A.; Holcomb, Kevin; Chapman‐Davis, Eloise

doi:10.1002/cncr.31856

Cited by 14 publications

(14 citation statements)

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“…founder mutations [12]. Extensive analyses have revealed that somatic BRCA1 mutations are uncommon in unselected patients, although expression of BRCA1 is often reduced, in non-hereditary (sporadic) BC [10,[12][13][14][15]. BRCA mutation and hormone receptor status are also interlinked.…”

Section: Dna Repair Parp Inhibition and Synthetic Lethalitymentioning

confidence: 99%

“…Germline BRCA (gBRCA) mutations are particularly common in certain populations. For example, in a study of 732 women of Ashkenazi Jewish heritage who underwent genetic testing, 11% had one of three gBRCA founder mutations [ 12 ]. Extensive analyses have revealed that somatic BRCA1 mutations are uncommon in unselected patients, although expression of BRCA1 is often reduced, in non-hereditary (sporadic) BC [ 10 , 12 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

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An Overview of PARP Inhibitors for the Treatment of Breast Cancer

2021

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Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.

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Section: Dna Repair Parp Inhibition and Synthetic Lethalitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

2021

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“…[4][5][6][7][8][9][10][11][12][13][14] The well-known founder mutations are BRCA1 185delAG, 5382insC and BRCA2 6174delT, 5,6 the three founder mutations account for more than 78% of BRCA1/2 pathogenic variants in the Ashkenazi Jewish population. 7,8 Other founder mutations have also been reported in Iceland (BRCA2 c.771_775del), 9 the Netherlands (BRCA1 c.2685_2686del) 10 and Sweden (BRCA1 c.3052_3053insTGAGA). 11 Despite the availability of substantial information regarding BRCA1/2 founder mutations in Caucasians, 4 the information available on BRCA1/2 founder mutations in Chinese Han is extremely limited.…”

Section: Introductionmentioning

confidence: 99%

“…Most BRCA1/2 founder mutation studies have been conducted in Caucasians . The well‐known founder mutations are BRCA1 185delAG, 5382insC and BRCA2 6174delT, the three founder mutations account for more than 78% of BRCA1/2 pathogenic variants in the Ashkenazi Jewish population . Other founder mutations have also been reported in Iceland ( BRCA2 c.771_775del), the Netherlands ( BRCA1 c.2685_2686del) and Sweden ( BRCA1 c.3052_3053insTGAGA) …”

Section: Introductionmentioning

confidence: 99%

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Meng

Yao

Yuan

et al. 2020

Intl Journal of Cancer

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The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity‐specific. Whether high‐frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next‐generation and/ or Sanger sequencing. Four hundred and seventy‐one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty‐seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease‐free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.

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“…Furthermore, it has been documented since several decades that Jewish women suffer from a genetic predisposition for BC. Ashkenazi Jewish patients, in fact, often develop a genetic (mutations in BRCA 1 and BRCA 2) or familial form of BC or ovarian cancer (42). Moreover, their response to chemoradiation can be less effective than the one registered in the rest of population (43).…”

Section: Resultsmentioning

confidence: 99%

The Holocaust Is a Significant and Independent Risk Factor of Late-Onset Cancers: A Systematic Review of the Literature and Original Data on Jewish Israeli, Jewish Non-Israeli and Non-Jewish Non-Israeli Survivors

Virgilio

Camilli²,

Gili³

et al. 2021

Anticancer Res

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Background/Aim: Seventy-six years after Auschwitz Liberation, the Holocaust keeps on persecuting its surviving victims. As witnessed by the psychiatric and medical literature in the last decades, in fact, the Holocaust survivors (HS) appear to suffer from several Shoah-related late-onset diseases impacting their survival, such as internal illnesses and posttraumatic stress disorder (PTSD). Cancer represents a further severe pathology which seems to be connected with the Holocaust experience. Our aim was to review the existing knowledge of Holocaust-related cancer in HS in order to assess its real incidence and clinicoprognostic significance. Materials and Methods: We systematically reviewed the literature dealing with Israeli Jewish and non-Jewish non-Israeli HS developing cancer. We also reviewed and analyzed the cancer data of noted Jewish HS not resident or having resided in Israel available as public information. Results: We found 16 and 15 studies on Israeli Jews and non-Jewish non-Israeli survivors, respectively.A statistically significant association between the Holocaust and development of late-onset cancer in HS was seen in most studies with cancer adversely impacting the survival. We also selected 330 noted Jewish non-Israeli HS: genocide-related late-onset cancer resulted to be a significant and independent risk factor of poor prognosis (p<0.0001) imparting shorter survival in affected versus non-cancer subjects (57 versus 64 years, respectively, p=0.0001). Conclusion: Although 76 years have passed, our review shows how the Holocaust keeps on burdening its survivors. Moreover, we offered the first analysis of Jewish HS not resident or having resided in Israel in terms of genocide-related late-onset diseases focusing on cancer. Further studies on Jewish non-Israeli HS are needed in order to corroborate our findings on late-onset cancer occurring in this targeted population.The Holocaust undoubtedly represents one of the darkest pages in the history of mankind: still today, European concentration and extermination camps, the ghettos and all the Memorial sites are steeped in horrors and crimes perpetrated by the Nazi Germany (1). Interestingly, differently from other past or current genocides, only the Shoah was characterized by a systematic and dehumanized medicalization of the sufferings (1, 2). To the physicians and medical students of today, in fact, it is emotionally and rationally shocking to know that the atrocities inflicted in anus mundi were realized with the active complicity of the German medical community and that, with very few notable exceptions, history has ignored 2745 This article is freely accessible online.

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Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

Cited by 14 publications

References 36 publications

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

The Holocaust Is a Significant and Independent Risk Factor of Late-Onset Cancers: A Systematic Review of the Literature and Original Data on Jewish Israeli, Jewish Non-Israeli and Non-Jewish Non-Israeli Survivors

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