Abstract 2935
Background
POLE proofreading mutations cause ultrahypermutant-phenotype in colorectal cancer (CRC) but the characters of POLE mutations are still obscure in contrast to Lynch syndrome or sporadic microsatellite instability (MSI). Herein, we examined mutation profiles of POLE in 1,039 CRC Japanese patients, and tried to clarify clinico-pathological features of hypermutant CRC patients with respect to POLE mutations, Lynch syndrome and sporadic MSI.
Methods
We analyzed POLE pathogenic hotspot (exon9, 13 and 14), BRAF codon 600 and KRAS exon 2 mutations by Sanger sequencing. MSI status was confirmed by a multiplex PCR assay. MSI positive cases were confirmed the four mismatch repair (MMR) proteins (MLH1, MSH2, PMS2, and MSH6) expression. Germline mutations were analyzed by Sanger sequencing and a TruSight One Sequencing Panel using a next generation sequencer.
Results
Of 1,039 CRC patients, only four cases showed POLE pathogenic mutations (two P286R, one V411L and one S459F). The four POLE-mutant CRCs showed no MSI. CRC with MMR deficient (=MSI) were observed in 58 cases (5.6%). Of CRCs with MSI, Lynch syndrome was found in 17 cases and the rest of 41 cases were sporadic MSI. Therefore, we divided 1,039 CRCs into the four subsets; POLE-mutant (POLE; n = 4, 0.4%), Lynch syndrome (LS; n = 17, 1.6%), sporadic MSI (MSI; n = 41, 4.0%), and non-hypermutant CRCs (NH; n = 997, 94.0%). Mean age at diagnosis in POLE/LS/MSI/NH was 52.5/55.7/73.6/65.9 years, respectively (P< .0001). Frequency of female in POLE/LS/MSI/NH was 50/23.5/61/41% (P = 0.03). The primary tumor located at the right colon was observed in 100/35/80.5/30% of POLE/LS/MSI/NH (P< .0001). BRAF mutation was observed in 49% of MSI and 4% of NH while KRAS mutation was in 35% of LS and 32% of NH (P< .0001). Interestingly, 100/82/78% of POLE/LS/MSI tumors were diagnosed at the earlier stage, I or II, while 46% of NH (P< .0001). The recurrence free survival rate at 5-years was better in POLE (100%)/LS (86%)/MSI (94%) compared with that in NH (74%).
Conclusions
POLE-mutant CRC was rare, observed in the younger without family history, located at the right colon, and diagnosed at the earlier stage.
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
The Ministry of Education, Culture, Sports, Science and Technology (MEXT).
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1159 - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome
Presenter: Elisenda Llabres Valenti
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3725 - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3708 - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5057 - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer
Presenter: Soodabeh Shahid Sales
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5970 - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR
Presenter: KARISHMA BAKSHI
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1360 - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma
Presenter: Hanhee Jo
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1634 - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System
Presenter: Yang Ge
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4921 - Measuring the Efficiency of Cancer Care in Europe
Presenter: Rikard Althin
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1235 - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients
Presenter: Chih-Yung Yang
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5169 - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.
Presenter: Natalia Levitskaya
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract