FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Nguyen-Dumont, Tú; Myszka, Aleksander; Karpiński, Paweł; Sasiadek, Maria M.; Akopyan, Hayane; Hammet, Fleur; Tsimiklis, Helen; Park, Daniel J.; Pope, Bernard J.; Ślężak, Ryszard; Kitsera, Nataliya; Siekierzyńska, A; Southey, Melissa C.

doi:10.1186/s12881-018-0524-x

Cited by 22 publications

(12 citation statements)

References 16 publications

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“…Notably, apart from breast and ovarian cancer, various other cancer types had been diagnosed in some families with FANCM mutations, including prostate cancer in the father of a female with breast cancer. 52 As our data displayed high expression of FANCM protein in the fibromuscular stroma of prostate, the relevance of FANCM mutations in the context of prostate cancer is alerted.…”

Section: Discussionmentioning

confidence: 70%

“…Consistent with the mouse models exhibiting increased tumor susceptibility, numerous recent studies in humans have linked homo-and heterozygous LoF variants in the FANCM with doubled risk to familial breast and ovarian cancer. 38,[47][48][49][50][51] These reports include the maternally inherited frameshift variant (p.Gln498Thrfs*7) detected in the Estonian index brothers, 52 the p.Arg1931* identified in the Portuguese case subject 4, and the p.Gln1701* nonsense mutation present in the Estonian case subject 3 and the two Finnish sisters with POI. 48,51 Unfortunately, the available family data on the case subjects in the current study did not enable assessment of the risk of different tumors.…”

Section: Discussionmentioning

confidence: 99%

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Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Kasak

Punab

Nagirnaja

et al. 2018

The American Journal of Human Genetics

113

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Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs7 (rs761250416) and a previously undescribed splicing variant (c.4387-10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701; rs147021911) and another from Portugal (p.Arg1931; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Kasak

Punab

Nagirnaja

et al. 2018

The American Journal of Human Genetics

113

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“…However, the role of monoallelic mutations in the remaining FA genes regarding cancer predisposition is a matter of discussion. Over the last few years, several case-controls studies have indicated that monoallelic FANCM [7][8][9][10][11][12][13][14][15] truncating mutations are breast cancer risk factors; in addition, there are inconsistent results regarding FANCA [16][17][18][19], FANCC [20][21][22][23][24], SLX4 [25][26][27] and XRCC2 [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Valle

Rofes

Moreno-Cabrera

et al. 2020

Cancers

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Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4–6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.

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“…Kwong et al [ 3 ] screened a cohort of breast cancer patients of Southern Chinese origin for RECQL variants by targeted sequencing of all coding exons. Nguyen-Dumont et al [ 4 ] used a similar strategy to screen breast and ovarian cancer patients from Poland and Ukraine. Li et al [ 5 ] performed similar screening in a cohort of Australian patients with a family history of breast cancer and a personal history of breast (> 95%) or ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of germline mutations in breast cancer genes: RECQL

Bowden

Tischkowitz

2019

Breast Cancer Res Treat

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Background The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL , a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations. Results The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1–2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case–control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case–control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants. Conclusions RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in ...

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FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Cited by 22 publications

References 16 publications

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Clinical implications of germline mutations in breast cancer genes: RECQL

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