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Oulun yliopiston väitöskirjat

BRCA/FANCONI ANEMIA PATHWAY GENES IN HEREDITARY PREDISPOSITION TO BREAST CANCER, ACTA UNIVERSITATIS OULUENSIS D Medica 1094

ISBN-13:	978-951-42-9408-2
Kieli:	englanti
Kustantaja:	Oulun yliopisto
Laitos:	Lääketieteellinen tiedekunta
Oppiaine:	Lääketiede,farmasia
Painosvuosi:	2011
Sidosasu:	pehmeäkantinen
Sijainti:	Print Tietotalo
Sivumäärä:	160
Tekijät:	SOLYOM SZILVIA

21.00 €

Two major genes are involved in hereditary predisposition to breast and ovarian cancer – BRCA1and BRCA2. However, germline mutations in these tumor suppressors account for a maximum20% of the familial breast cancer cases. A significant portion of the genes predisposing to thisdisease is unknown and therefore needs to be discovered. The aim of this study was to identifynovel breast cancer susceptibility genes from the interweaving BRCA/Fanconi anemia (FA)pathway. Five candidate genes – MERIT40, ABRAXAS, BRIP1, CHK1, and FANCA – werescreened for mutations by utilizing conformation-sensitive gel electrophoresis and sequencing, orwith multiplex ligation-dependent probe amplification in blood DNA samples of Finnish familialbreast cancer patients. Investigation of the MERIT40 gene revealed novel nucleotide changes, being the first report onmutation screening of this gene. None of the observed alterations, however, appeared to be diseaserelated, suggesting that germline mutations in MERIT40 are rare or absent in breast cancerpatients. A missense alteration (c.1082G>A, leading to Arg361Gln) was identified in ABRAXAS in 3 outof 125 Northern Finnish breast cancer families (2.4%), but not in any of the 867 healthy controls.The prevalence of the mutation between familial and control cases was statistically significantlydifferent (p=0.002). ABRAXAS c.1082G>A appears to have pathological significance based on itsexclusive occurrence in cancer cases, evolutionary conservation, disruption of a putative nuclearlocalization signal, reduced nuclear localization of the protein, and defective accumulation atDNA damage sites. The BRIP1 (FANCJ) and CHK1 genes were screened for large genomic rearrangements, butno abnormalities were detected, ruling out a significant contribution to breast cancer susceptibilityin the Northern Finnish population. A novel large heterozygous deletion was identified in the FANCA gene in one out of 100 breastcancer families, removing the promoter and the first 12 exons. The deletion allele was not presentin the tested controls, suggesting that it might contribute to breast cancer susceptibility. This is thefirst report on the association of a large-size germline deletion in a gene acting in the upstream partof the FA signaling pathway with familial breast cancer.

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