The findings, led by Jordi Surralles, Professor at the University at Autonoma de Barcelona, showed that the genetic syndrome is caused by mutations in both copies of the FANCM
gene - also known as biallelic mutations.
To do this they investigated three human genes associated with cancer development: FANCM (mutations of which are associated with blood cancers), BRCA1 (mutations of which are commonly found in patients with breast and ovarian cancers), and BLM (mutations of which cause a variety of cancers).
FANCM, known to repair DNA damage where two DNA strands have been incorrectly linked, was removed from cells also deficient of BRCA1 or BLM.
Genes Tested AtP ALK APC ATM BAP1 BRCA2 BRIP1 BUB1B CDC73 CDH1 CEP57 CHEK2 CYLD DDB2 DICER1 ERCC3 ERCC4 ERCC5 EXT1 EXT2 FANCD2 FANCE FANCF FANCG FANCI GATA2 GPC3 HNF1A HOXB13 HRAS MLH1 MHS2 MSH6 MUTYH NBN PHOX2B PMS1 PMS2 PPM1D PRF1 RAD51D RBI RECQL4 RET RHBDF2 SDHC SDHD SLX4 SMAD4 SMARCA4 TP53 TSC1 TSC2 VHL WT1 BARD1 BLM BMPR1A BRCA1 CDK4 CDKN1C CDKN2A CEBPA DI53L2 EGFR EPCAM ERCC2 EZH2 FANCA FANCB FANCC FANCL FANCM
FH FLCN KIT MAX MEN1 MET NF1 NF2 NSD1 PALB2 PRKAR1A PTCH1 PTEN RAD51C RUN XI SBDS SDHAF2 SDHB SMARCB1 STK11 5UFU TMEM127 WRN XPA XPC This chart shows all 98 cancer susceptible genes included in this new test.
Among these genes, 9 [aprataxin (APTX), aprataxin and PNKP like factor (APLF), X-ray repair cross complementing 4 (XRCC4), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM), damage specific DNA binding protein 2 (DDB2), XPC complex subunit, DNA damage recognition and repair factor (XPC), and mutL homolog 3 (MLH3)] were over-expressed in CTC-MCC-41 cells and only 4 [DNA polymerase mu (POLM), RAD51 recombinase (RAD51), ERCC excision repair 1 (ERCC1), and tumor protein p53 binding protein 1 (TP53BP1)] in HT-29 cells.
Interestingly, among the 1624 transcripts (see online Supplemental Table S8) exclusively upregulated in CTC-MCC-41 samples, key genes related to energy metabolism such as (PPARGC1A, PPARGC1B, FABP1, ALDH3A, ALDH2, AOX1, and ABCB1), DNA repair (BRIP1, FANCM, XRCC4, DDB2, and XPC), and stemness genes including GLS2, ZNF93, and B3GNT7were observed.
Prevalence of TP53 mutations in BRCA1 and 2 negative young Pakistani BC patients (=30 years) was assessed, uncovering novel mutations which can account for a subset of cancers occurring in the younger age group.45An association between vitamin D receptor Cdx-2 gene polymorphism and risk of breast cancer in premenopausal women revealed an increased risk of BC in young women with GG genotype,46 while another study reported a reduced expression of metastasis suppression genes (KiSS1 and KAL1) in Pakistani BC patients.47 Absence of FANCM c.
Absence of the FANCM c.5101C andgt:T mutation in BRCA1 /2-negative triple-negative breast cancer patients from Pakistan.
Keck, "Defining the molecular interface that connects the Fanconi anemia protein FANCM
to the Bloom syndrome dissolvasome," Proceedings of the National Academy of Sciences of the United States of America, vol.
Deans, analysed the FA gene FANCM as it directly binds to DNA and has been known to have specificity for substrates that are alike those linked with the BS core complex.
Scientists recognized two regions in the FANCM protein that physically linked the FA core complex and the BS complex.
For example, the FANCM
protein detects the stalled replication fork caused by interstrand crosslinks (ICLs); the MRN complex is the typical sensor of DSBs during S/G2 phase; the Ku70/Ku80 heterodimer is the primary DSBs sensor during G1, while replication protein A (RPA) overcoats single-strand DNA (ssDNA) found either at processed DSB overhangs to be repaired by HR or at stalled replication forks .