Functional and physical interaction between the mismatch repair and FA-BRCA pathways

Williams, Stacy; Wilson, James B.; Clark, Allison; Mitson-Salazar, Alyssa; Tomashevski, Andrei; Ananth, Sahana; Glazer, Peter M.; Semmes, O. John; Bale, Allen E.; Jones, Nigel J.; Kupfer, Gary M.

doi:10.1093/hmg/ddr366

Cited by 52 publications

(48 citation statements)

References 68 publications

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“…34 The pivotal FA protein FANCD2 was subsequently shown to interact with MSH2 and MLH1. 35 Our report indicates that the presence of biallelic BRCA2 mutations should be considered in families with early-onset breast and CRCs, even in the absence of cardinal features of FA.…”

Section: Early-onset Crcs and Biallelicmentioning

confidence: 64%

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

et al. 2013

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Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A4G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A4G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A4G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

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Section: Early-onset Crcs and Biallelicmentioning

confidence: 64%

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

et al. 2013

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“…Although the type of DNA lesion preferentially targeted by each mechanism is known, 183 notably, there is evidence for direct interaction between components of the different repair systems as well as between DNA repair and the p53 pathway. [186][187][188][189][190][191][192][193][194] Although loss of apoptotic/senescent function in theory should be expected to cause therapy resistance, the opposite may be the case in DNA repair. Drugs like alkylating agents generate 8-oxoguanine and single-strand breaks subject to repair by BER, whereas platinum-containing compounds generate interstrand crosslinks and double-strand breaks.…”

Section: Dna Repair Pathwaysmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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“…Another important non-BRCA1/BRCA2 (55). FA is a rare autosomal or X-linked recessive genetic heterogeneous disorder characterized by spontaneous chromosomal breaks, abnormal DNA repair and clinical problems including congenital abnormalities, endocrinopathies, early onset bone marrow failure and an increased susceptibility to cancer and leukemia (36). Similar to BRCA, the FA proteins form a functional core complex and are associated with a novel pathway required for DNA damage repair, particularly DNA interstrand cross-links.…”

Section: Lynch Syndromementioning

confidence: 99%

“…1, BRCA1 forms a multi-subunit protein complex, which includes DNA damage repair proteins, including FA and MMR proteins. Recent studies showed a functional interaction between FANCJ and the MMR complex MutL α, which is essential for establishment of DNA interstrand cross-links (36). FANCD2 is required for binding between MSH2 and MLH1, which are involved in the monoubiquitination of FANCD2, leading to recruitment of ATR and then activation of CHK1 and TP53.…”

Section: Lynch Syndromementioning

confidence: 99%

Hereditary breast and ovarian cancer susceptibility genes (Review)

et al. 2013

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Abstract. Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER-and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed 'BRCAness', those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.

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Functional and physical interaction between the mismatch repair and FA-BRCA pathways

Cited by 52 publications

References 68 publications

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Hereditary breast and ovarian cancer susceptibility genes (Review)

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