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. 2017 Sep;3(5):a001487.
doi: 10.1101/mcs.a001487. Epub 2017 May 3.

A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents

David C Wilkes  1 , Verena Sailer  2 , Hui Xue  3   4 , Hongwei Cheng  3   4 , Colin C Collins  3   4 , Martin Gleave  3   4 , Yuzhuo Wang  3   4 , Francesca Demichelis  5 , Himisha Beltran  6   7 , Mark A Rubin  1   2   7 , David S Rickman  1   2   7
Affiliations

A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents

David C Wilkes et al. Cold Spring Harb Mol Case Stud. 2017 Sep.

Abstract

Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies. A previous report revealed an association between an exceptional response to cisplatin treatment and a somatic loss of heterozygosity (LOH) of FANCA in a patient with metastatic prostate cancer who also harbored a germline FANCA variant (S1088F). Although germline FANCA mutations are the most frequent alterations in patients with Fanconi anemia, germline alterations are less common in prostate cancer VSports手机版. We hypothesized that the germline S1088F FANCA variant in combination with FANCA LOH was deleterious for FANCA function and contributed to the patient's exceptional response to cisplatin. We show that although it properly localizes to the nucleus, the S1088F FANCA mutant protein disrupts the FANC protein complex resulting in increased sensitivity to DNA damaging agents. Because molecular stratification is emerging as a strategy for treating men with metastatic, castrate-resistant prostate cancer harboring specific DDR gene defects, our findings suggest that more biomarker studies are needed to better define clinically relevant germline and somatic alterations. .

Keywords: prostate cancer V体育安卓版. .

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Figures

Figure 1.
Figure 1.
(A) Western blot of FANCA expression levels in isogenic cell lines. The graph indicates fold difference in the level of FANCA protein normalized to the FANCA endogenous control (* specifies P < 0.0439). (B) Drug sensitivity to cisplatin representing IC50 of null, wild-type, and S1088F cell lines (* specifies significant difference P < 0.004). (C) Drug sensitivity to mitomycin C (MMC) illustrating the IC50 (* indicates significant difference P < 0.006).
Figure 2.
Figure 2.
(A) Western blot expression of FANCD2 with 1 µM mitomycin C (MMC) treatment or vehicle. Arrow indicates monoubiquitinated isoform and lower band is the nonubiquitinated FANCD2 protein. Longer/shorter (L/S) ratios are also included. (B) Bar graph specifies the percentage of monoubiquitinated FANCD2 with and without MMC treatment (* specifies significant difference P < 0.328). (C) Western blot expression of FANCD2 and FANCI with 1 µM MMC treatment.
Figure 3.
Figure 3.
(A) The graph shows the percentage of cells whose nuclei are identified as having five or greater FANCD2 foci with either vehicle or 1 µM mitomycin C (MMC) treatment. Fisher exact tests between wild-type FANCA and S1088F were performed and a significant difference was marked (*, P < 0.0211). (B) Typical FANCD2 foci formation in 1 µM MMC-treated cell lines: (left to right) B1 FANCA null, B2 FANCA wild type, and B3 FANCA S1088F cell lines. Blue, DAPI; green, FANCD2. Scale bar, ∼10 µm.
Figure 4.
Figure 4.
Cellular localization of FANCA protein. Red, FANCA; blue, DAPI. Nuclear localization of null FANCA control showing no FANCA signal with (A) no mitomycin C (MMC) and (B) 1 mM MMC. Nuclear localization of wild-type FANCA with (C) no MMC and (D) 1 mM MMC. Nuclear locatization of FANCA in the S1088F FANCA cell line with (E) no MMC and (F) 1 mM MMC. Scale bar, ∼10 µm.
Figure 5.
Figure 5.
(A) Dose–response to olaparib indicating the IC50 of null, wild-type, and S1088F (* specifies significant difference P < 0.0373). (B) Growth of the patient-derived xenograft (PDX) from patient PM12 (LTL545) with and without olaparib treatment over 18 d (*, P < 0.0001).
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References

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