Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer

Webster, Andrew L. H.; Sanders, Mathijs A.; Patel, Kaustubh; Dietrich, Ralf; Noonan, Raymond J.; Lach, Francis P.; White, Ryan R.; Goldfarb, Audrey; Hadi, Kevin; Edwards, Matthew; Donovan, Frank X.; Hoogenboezem, Remco M.; Jung, Moonjung; Sridhar, Sunandini; Wiley, Tom; Fédrigo, Olivier; Tian, Huasong; Rosiene, Joel; Heineman, Thomas E.; Kennedy, Jennifer A.; Bean, Lorenzo; Rosti, Rasim Özgür; Tryon, Rebecca; Gonzalez, Ashlyn-Maree; Rosenberg, Allana; Luo, Ji‐Dung; Carroll, Thomas; Shroff, Sanjana; Beaumont, Michael; Velleuer, Eunike; Rastatter, Jeff C.; Wells, Susanne I.; Surrallés, Jordi; Bagby, Grover C.; MacMillan, Margaret L.; Wagner, John E.; Cancio, Maria; Boulad, Farid; Scognamiglio, Theresa; Vaughan, Roger; Beaumont, Kristin G.; Koren, Amnon; Imieliński, Marcin; Chandrasekharappa, Settara C.; Auerbach, Arleen D.; Singh, Bhuvanesh; Kutler, David I.; Campbell, Peter J.; Smogorzewska, Agata

doi:10.1038/s41586-022-05253-4

Cited by 42 publications

(34 citation statements)

References 80 publications

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“…Foldback inversions have been detected in a variety of human cancers, including pancreatic, ovarian, breast, and squamous cell carcinomas (SCC), and are associated with poor prognosis 62,63,64,65,66,67,68 . The mechanism by which these foldback inversions form is unknown and could involve the foldback priming mechanism described here, particularly in tumors with mutations in MRE11, RAD50 or NBS1.…”

Section: Discussionmentioning

confidence: 99%

Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ and Rad51-dependent mechanism

Al-Zain

Nester

2023

Preprint

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Inverted duplications, also known as foldback inversions, are commonly observed in cancers and are the major class of chromosome rearrangement recovered from yeast cells lacking Mre11 nuclease. Foldback priming at naturally occurring inverted repeats is one mechanism proposed for the generation of inverted duplications. However, the initiating lesion for these events and the mechanism by which they form has not been fully elucidated. Here, we show that a DNA double-strand break (DSB) induced near natural short, inverted repeats drives high frequency inverted duplication in Sae2 and Mre11-deficient cells. We find that DNA polymerase delta proof-reading activity acts non-redundantly with Rad1 nuclease to remove heterologous tails formed during foldback annealing. Additionally, Pol32 is required for the generation of inverted duplications, suggesting that Pol delta catalyzes fill-in synthesis primed from the foldback to create a hairpin-capped chromosome that is subsequently replicated to form a dicentric isochromosome. Stabilization of the dicentric chromosome after breakage involves telomere capture by non-reciprocal translocation mediated by repeat sequences and requires Rad51.

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Section: Discussionmentioning

confidence: 99%

Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ and Rad51-dependent mechanism

Al-Zain

Nester

2023

Preprint

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“…We propose that biallelic RAD51C mutations and defects in DNA damage response result in a 'hypermutator phenotype' with the accumulation of postzygotic de novo mutations. Recently reported mutational spectrum of squamous cell carcinoma from individuals with FA showed a collection of somatic SV, with exposure to tobacco and alcohol mutagens overwhelming the ability of a defective DNA repair pathway (Webster et al 2022). The absence of major SV in our patient could be due to the more stringent selection pressure that occurs during embryonic development compared to selection for cancer cells.…”

Section: Discussionmentioning

confidence: 99%

SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia

Zemet

Gambin

et al. 2023

Hum Genet

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We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5%-37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the rare phenomenon of hypermutation. Eight-hundred-thirty apparent dnSNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants.The VAFs showed a bimodal distribution, with one component with an average VAF of 25% (range: 18.7-37.41%) (n=446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range: 9.55-18.69%) (n=384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA, and pregnancy loss in general. We propose that other FA groups should be investigated for genome-wide de novo variants.

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“…FA is a model syndrome of genome instability and is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage. Cancer derived from FA present of high numbers of structural variants [198]. FA is caused by biallelic mutations in at least 12 different genes, some of which form a nuclear core complex that involves the ubiquitination of the central FANCD2 protein.…”

Section: Impairment Of Dna Damage Repair Pathwaysmentioning

confidence: 99%

“…Biallelic mutations in BRCA2 and FANCD2 can lead to a severe FA-like phenotype. The FA genes and FANC2 are involved in DNA repair functions that are associated with the resolution of DNA crosslinks and stalled replication forks [199]. Although genetic instability caused by mutations in the FANC genes can be detrimental for most FA patients, around 20% appear to benefit from it, as it increases the chance of somatic reversion of their constitutional mutations.…”

Section: Impairment Of Dna Damage Repair Pathwaysmentioning

confidence: 99%

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution

Comaills¹,

Castellano‐Pozo²

2023

Preprint

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The integrity of the genome is crucial for the survival of all living organisms. However, genomes need to adapt to survive certain pressures and for this propose use several mechanisms to diversify. Chromosomal instability (CIN) is one of the main mechanism leading to the creation of genomic heterogeneity by altering the number of chromosomes as well as changing their structures. In this review we will discuss the different chromosomal patterns and changes observed in speciation, in evolutional biology as well as during tumor progression. By nature, human genome shows induction of diversity during gametogenesis but as well during tumorigenesis that can conclude in drastic changes such as whole genome doubling to more discrete changes as indels as well as the recent discovered complex chromosomal rearrangement chromothripsis. More importantly, changes observed during speciation are strikingly similar to the genomic evolution observed during tumor progression and resistance to therapy. The different origins of CIN will be treated as the importance of double strand breaks (DSB) or the consequences of micronuclei. We will also explain the mechanisms behind the controlled DSBs and recombination of homologous chromosomes observed during meiosis, to explain how errors lead to similar pattern observed during tumorigenesis. Then, we will also list several diseases associated to CIN resulting in fertility issue, miscarriage, genetic rare diseases and cancer. Understanding better chromosomal instability as a whole is primordial for the understanding of mechanisms leading to tumor progression.

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Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer

Cited by 42 publications

References 80 publications

Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ and Rad51-dependent mechanism

Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ and Rad51-dependent mechanism

SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution

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