TY - JOUR
T1 - Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations
AU - Selenica, Pier
AU - Alemar, Barbara
AU - Matrai, Cathleen
AU - Talia, Karen L.
AU - Veras, Emanuela
AU - Hussein, Yaser
AU - Oliva, Esther
AU - Beets-Tan, Regina G. H.
AU - Mikami, Yoshiki
AU - McCluggage, W. Glenn
AU - Kiyokawa, Takako
AU - Weigelt, Britta
AU - Park, Kay J.
AU - Murali, Rajmohan
N1 - Funding Information:
Conflict of interest BW is supported in part by Breast Cancer Research Foundation and Stand Up to Cancer grants. The authors have no other relevant disclosures or conflicts of interest.
Funding Information:
Acknowledgements We are grateful to the Integrated Genomics Operation at Memorial Sloan Kettering Cancer Center for their assistance with sequencing. This work was funded in part by a Cycle for Survival grant (to RM, KJP and BW), and in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
PY - 2021/6
Y1 - 2021/6
N2 - Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p <0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p <0.05) and IGAs (41% vs 57%, p <0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p <0.05) and IGAs (10% vs 1%, p <0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p <0.01) compared to PAs, and in CDKN2A (18% vs 1%, p <0.05) and KRAS (18% vs 6%, p <0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.
AB - Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p <0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p <0.05) and IGAs (41% vs 57%, p <0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p <0.05) and IGAs (10% vs 1%, p <0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p <0.01) compared to PAs, and in CDKN2A (18% vs 1%, p <0.05) and KRAS (18% vs 6%, p <0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.
KW - ENDOCERVICAL GLANDULAR HYPERPLASIA
KW - COPY NUMBER
KW - UTERINE CERVIX
KW - CANCER
KW - P53
KW - INHIBITOR
KW - DISCOVERY
KW - DNA
KW - IMMUNOPHENOTYPE
KW - PREVALENCE
U2 - 10.1038/s41379-020-00726-1
DO - 10.1038/s41379-020-00726-1
M3 - Article
C2 - 33318584
SN - 0893-3952
VL - 34
SP - 1213
EP - 1225
JO - Modern Pathology
JF - Modern Pathology
IS - 6
ER -