BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.
BACKGROUND
Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain.


METHODS
Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed.


RESULTS
Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history.


CONCLUSIONS
Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.
Division of Gynecologic Oncology, University of Washington Medical Center, Seattle, Washington 98195-6460, USA.
Kathryn P
KP
Pennington
Tom
T
Walsh
Ming
M
Lee
Christopher
C
Pennil
Akiva P
AP
Novetsky
Kathy J
KJ
Agnew
Anne
A
Thornton
Rochelle
R
Garcia
David
D
Mutch
Mary-Claire
MC
King
Paul
P
Goodfellow
Elizabeth M
EM
Swisher
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases