Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (28864460)
Authors Wilkes DC, Sailer V, Xue H, Cheng H, Collins CC, Gleave M, Wang Y, Demichelis F, Beltran H, Rubin MA, Rickman DS
Title A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents.
Journal Cold Spring Harbor molecular case studies
Vol 3
Issue 5
Date 2017 Sep
URL
Abstract Text 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. 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FANCA S1088F missense unknown FANCA S1088F lies within the leucine zipper domain of the Fanca protein (PMID: 22194614). The functional effect of S1088F is conflicting as it results in decreased Fancd2 and Fanci monoubiquitination and decreased DNA repair in response to mitomycin C treatment in culture in one study (PMID: 28864460), but restores Fancd2 monoubiquitination, confers resistance to mitomycin C-induced cell death and G2/M cell cycle block to levels similar of wild-type protein in FANCA-null cells in another study (PMID: 31586946).
FANCA T1131A missense unknown FANCA T1131A does not lie within any known functional domains of the Fanca protein (UniProt.org). the functional effect of T1131A is conflicting as it demonstrates nuclear localization, Fancc binding, Fancd2 monoubiquitination, and complementation of cellular sensitivity to mitomycin C similar to wild-type Fanca protein in culture (PMID: 12444097), but in another study, results in impaired Fancd2 monoubiquitination (PMID: 28864460), and therefore, its effect on Fanca protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FANCA S1088F Advanced Solid Tumor sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, overexpression of FANCA S1088F in FANCA-null cells derived from Fanconi anemia patients resulted in increased sensitivity to Platinol (cisplatin) compared to wild-type Fanca expression in culture (PMID: 28864460). 28864460
FANCA S1088F prostate cancer predicted - sensitive Olaparib Preclinical - Pdx Actionable In a preclinical study, overexpression of FANCA S1088F in FANCA-null cells derived from Fanconi anemia patients resulted in increased sensitivity to Lynparza (olaparib) in culture, and a patient-derived xenograft (PDX) model of prostate cancer harboring germline FANCA S1088F demonstrated enhanced sensitivity to Lynparza (olaparib) treatment (PMID: 28864460). 28864460