<i>FANCM</i> c.5101C&gt;T mutation associates with breast cancer survival and treatment outcome

Kiiski, Johanna I.; Fagerholm, Rainer; Tervasmäki, Anna; Pelttari, Liisa M.; Khan, Sofia; Jamshidi, Maral; Mantere, Tuomo; Pylkäs, Katri; Bártek, Jiří; Bártková, Jiřina; Mannermaa, Arto; Tengström, Maria; Kosma, Veli‐Matti; Winqvist, Robert; Kallioniemi, Anne; Aittomäki, Kristiina; Blomqvist, Carl; Nevanlinna, Heli

doi:10.1002/ijc.30394

Cited by 13 publications

(9 citation statements)

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“…Although recent works established a link between the heterozygous c.5101C>T FANCM truncating mutation and BOC predisposition in the Finnish population ( Kiiski et al, 2016 , 2014 ; Neidhardt et al, 2017 ), there is no history of BOC in the family investigated here. Interestingly, a few apparently healthy (i.e., without cancer) individuals homozygous for the c.5101C>T FANCM mutation were identified in previous studies ( Kiiski et al, 2016 , 2014 ; Neidhardt et al, 2017 ). Indeed, the authors stated, by direct observation or by looking at registered clinical data, that none of them presented FA stigmata (although no data on age, sex or clinical findings was made available).…”

Section: Discussionmentioning

confidence: 64%

A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

Fouquet

Pawlikowska

Caburet

et al. 2017

eLife

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Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients’ lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

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Section: Discussionmentioning

confidence: 64%

A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

Fouquet

Pawlikowska

Caburet

et al. 2017

eLife

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“…In the Finnish population, p.Gln1701* was found to be associated with breast cancer risk with an odds ratio (OR) of 1.86 and with greater effects in familial cases, and for estrogen receptor-negative (ER-negative) and triple-negative breast cancer (TNBC) subtypes [5]. This variant was later found to be also associated with breast cancer survival and treatment outcome [6]. A second FANCM PTV, the c.5791C > T (p.Gly1906Alafs12*, rs144567652), which is annotated and hereafter referred to as p.Arg1931*, showed association with breast cancer risk in familial cases with OR = 3.93 [7].…”

Section: Introductionmentioning

confidence: 99%

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Figlioli¹,

Kvist²,

Tham³

et al. 2020

Cancers

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Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

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“…The two most common FANCM variants we observed are more common in European populations than other world populations. These variants were both first identified in European ancestry BRCA1/2-negative familial breast cancer studies, 46,47 and both have previously been associated with ER-negative or triple negative breast cancer. 46,48,49 Additionally, rs147021911 (chr14:45658326C>T, c.5101 C >T, p.Gln1701*) was associated with poor breast cancer survival in a Finnish population, 50 and other FANCM LoF mutations were found in small breast cancer case series, [51][52][53][54][55] including a study that showed bi-allelic FANCM variants in early onset or bilateral breast cancer cases.…”

Section: Discussionmentioning

confidence: 94%

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifiesFANCMas a susceptibility gene for estrogen-receptor-negative breast cancer

Nierenberg

Adamson

et al. 2023

Preprint

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Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes.Methods: We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk.Results: We saw a strong association of LoF variants inFANCMwith ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes,BRCA1(p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]),BRCA2(p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), andPALB2(p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53.Conclusion: In H/L women, LoF variants inFANCMwere strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate thatFANCMshould be added to BC gene panels.

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome

Cited by 13 publications

References 50 publications

A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifiesFANCMas a susceptibility gene for estrogen-receptor-negative breast cancer

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