Inherited DNA repair gene mutations detected by tumor next generation sequencing in urinary tract cancers.
Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. sumati.gupta@hci.utah.edu.
Sumati
0000-0001-6271-0831
S
Gupta
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Samantha
S
Greenberg
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Jade
J
Grimmett
University of Utah School of Medicine, 30 N. 1900 E, Salt Lake City, UT, 84112, USA.
David
D
Gaston
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Neeraj
N
Agarwal
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
William
W
Lowrance
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Joshua
J
Schiffman
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Wendy
W
Kohlmann
D000328:Adult; D000368:Aged; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D000071796:SMARCB1 Protein / Q000235:genetics; D014571:Urologic Neoplasms / Q000235:genetics*
C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
BRCA2; FANCA; Inherited DNA repair defects; MUTYH; Next-generation sequencing; Urinary tract cancer