scholarly journals Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4317
Author(s):  
Peng-Chan Lin ◽  
Yu-Min Yeh ◽  
Hui-Ping Hsu ◽  
Ren-Hao Chan ◽  
Bo-Wen Lin ◽  
...  

Tumor heterogeneity results in more than 50% of hypermutated cancers failing to respond to standard immunotherapy. There are numerous challenges in terms of drug resistance, therapeutic strategies, and biomarkers in immunotherapy. In this study, we analyzed primary tumor samples from 533 cancer patients with six different cancer types using deep targeted sequencing and gene expression data from 78 colorectal cancer patients, whereby driver mutations, mutational signatures, tumor-associated neoantigens, and molecular cancer evolution were investigated. Driver mutations, including RET, CBL, and DDR2 gene mutations, were identified in the hypermutated cancers. Most hypermutated endometrial and pancreatic cancer patients carry genetic mutations in EGFR, FBXW7, and PIK3CA that are linked to immunotherapy resistance, while hypermutated head and neck cancer patients carry genetic mutations associated with better treatment responses, such as ATM and BRRCA2 mutations. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and DNA repair defects are mutational drivers that are signatures for hypermutated cancer. Cancer driver mutations and other mutational signatures are associated with sensitivity or resistance to immunotherapy, representing potential genetic markers in hypermutated cancers. Using computational prediction, we identified NF1 p.T700I and NOTCH1 p.V2153M as tumor-associated neoantigens, representing potential therapeutic targets for immunotherapy. Sequential mutations were used to predict hypermutated cancers based on genomic evolution. Using a logistic model, we achieved an area under the curve (AUC) = 0.93, accuracy = 0.93, and sensitivity = 0.81 in the testing set. The sequential patterns were distinct among the six cancer types, and the sequential mutation order of MSH2 and the coexisting BRAF genetic mutations influenced the hypermutated phenotype. The TP53~MLH1 and NOTCH1~TET2 sequential mutations impacted colorectal cancer survival (p-value = 0.027 and 0.0001, respectively) by reducing the expression of PTPRCAP (p-value = 1.06 × 10−6) and NOS2 (p-value = 7.57 × 10−7) in immunity. Sequential mutations are significant for hypermutated cancers, which are characterized by mutational heterogeneity. In addition to driver mutations and mutational signatures, sequential mutations in cancer evolution can impact hypermutated cancers. They characterize potential responses or predictive markers for hypermutated cancers. These data can also be used to develop hypermutation-associated drug targets and elucidate the evolutionary biology of cancer survival. In this study, we conducted a comprehensive analysis of mutational patterns, including sequential mutations, and identified useful markers and therapeutic targets in hypermutated cancer patients.

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1705
Author(s):  
Elena De Mattia ◽  
Jerry Polesel ◽  
Rossana Roncato ◽  
Adrien Labriet ◽  
Alessia Bignucolo ◽  
...  

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR:1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR:0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR:0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14576-e14576
Author(s):  
Xinlu Liu ◽  
Jiasheng Xu ◽  
Jian Sun ◽  
Deng Wei ◽  
Xinsheng Zhang ◽  
...  

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10056-10056
Author(s):  
Afsaneh Barzi ◽  
Dawn L. Hershman ◽  
Cathee Till ◽  
Heinz-Josef Lenz ◽  
Howard S. Hochster ◽  
...  

10056 Background: There are currently 1.5 million CRC survivors in US and this number will continue to rise with advancements in treatment. The risk of OP in CRC survivors has not been well described. Methods: We used data from 3 SWOG CRC treatment trials, all of which were phase III and had long term follow-up. Enrollees were linked to Medicare claim files for identification of OP and fractures using HCPCS and ICD9 codes. First, we compared patterns of osteoperosis and fracture risk by sex in colorectal cancer patients. To assess whether patterns of fracture risk by sex differed between patients with vs. without colorectal cancer, we compared the difference in fracture risk by sex in colorectal cancer patients to the difference in fracture risk by sex in the general U.S. population, using data from the National Health Interview Survey (NHIS) and the National Hospital Discharge Survey (NHDS). Finally, we assessed whether absolute estimates of osteoperosis and fracture risk differed between men with colorectal cancer and men without colorectal cancer. Comparison data for men without colorectal cancer were obtained from the placebo arm of the Prostate Cancer Prevention trial (PCPT). Results: We linked 1233 CRC cases with Medicare claims. The median age at CRC diagnosis was marginally higher for women (65 vs 64 ys, p = 0.03). 47% of females, 15% of men with CRC, and 19% of men without CRC had a OP diagnosis. The female to male ratio of osteoporotic fracture in general U.S. population was 1.67, while the same ratio in CRC survivors was 2.84, an increase of 70% (p-value < 0.001). Conclusions: Our study indicates that the risk disparity for OP fracture for females is much greater in CRC survivors than in the general U.S. population. This may be due to more OP diagnoses for female CRC survivors, but not for male CRC survivors.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9047-9047
Author(s):  
A. N. Amin ◽  
S. A. Stemkowski ◽  
J. Lin ◽  
G. Yang

9047 Background: This study evaluates whether clinicians are providing appropriate VTE prophylaxis to at-risk surgical and non- surgical cancer patients in accordance with ACCP guidelines. Methods: Premier's inpatient administrative data were used to assess VTE prophylaxis rates in fourteen cancer types. Patients age 40 or older, with a minimum length of stay of six days, and no contraindications for anti-coagulation were included in the study. Two rates were determined; the rate of discharges receiving any level of anticoagulation and the rate of patients receiving appropriate prophylaxis by comparing daily use of anti-coagulants and compression devices, dosage, and prophylaxis duration with ACCP recommendations. The 6th guidelines were used due to their release prior to the study period. Rates based on the 7th guidelines were calculated for the same patient cohort to assess how the revised guidelines affect our findings. Trends were assessed by comparing prophylaxis rates by quarter. Results: 72,391 discharges from 225 hospitals between January 2002 and September 2005 met the inclusion criteria. 29% of all at-risk cancer discharges received the recommended prophylaxis regimen. Rates varied by cancer type ranging from 18.7% in prostate to 36.3% in colorectal cancer discharges. 55% did not receive any anti-coagulation prophylaxis, 9.5% received insufficient dosage and 5.8% did not receive prophylaxis for the appropriate duration. The appropriate VTE prophylaxis rate is higher for surgical cancer than for non-surgical cancer discharges (32.3% vs. 27.7%). Trends suggest a slight increase in appropriate prophylaxis rates for all types of cancer discharges. Appropriate prophylaxis rates based on 7th guidelines are lower than rates based on the 6th guidelines due to the more specific recommendation in the 7th guidelines. Conclusions: Cancer patients are known to have significant risk for VTE, yet VTE prophylaxis for at-risk non-surgical cancer patients in hospitals is not optimal. Rates for surgical cancer patients were only slightly higher. Using the 7th recommendations results in lower prophylaxis rates. More effort is required to increase awareness of the ACCP recommendations for thromboprophylaxis in cancer patients. No significant financial relationships to disclose.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3069-3069
Author(s):  
Jianwen Qin ◽  
Dongsheng Shi ◽  
Lijie Song ◽  
Yan Yin ◽  
Bin Liu ◽  
...  

3069 Background: HER2 belongs to the same family with EGFR and is known as an important cancer driver gene. Kinase domain insertions and deletions (KD indels) are frequent driver mutations in both EGFR and HER2. The most common HER2 KD indels are the exon 20 insertions while others are rarely reported. Our study aimed to investigate the role of less common HER2 KD indels in solid tumors. Methods: This study was performed in 63,267 Chinese patients including 53,591 patients with lung cancer, 5,888 patients with colorectal cancer, 3,774 patients with breast cancer and 14 patients with renal pelvis cancer. Tissue or plasma samples from the patients were subjected to capture-based targeted sequencing covering HER2 and other cancer related genes. The sequencing data of each patient were retrospectively collected and analyzed. The HER2 exon 18/19 indels identified in our study were compared with data from COSMIC and MSKCC. In vitro analysis in Ba/F3 cell lines was performed to assess drug response of different HER2 exon 18/19 indels. Results: We identified recurrent HER2 KD indels in exon 18 and 19, with a frequency of 0.04% (25/63,267). The data from COSMIC and MSKCC reported the prevalence of HER2 exon 18/19 indels ranging from 0.04% to 0.23% among breast, cervical, and pancreatic cancers. In our study, HER2 exon 18/19 indels were identified in 20 patients with lung cancer (0.037%), two with colorectal cancer (0.034%), two with breast cancer (0.053%) and one with renal pelvis cancer (7.143%). Only two patients (8%) harbored concurrent actionable driver mutations including EGFR mutation and MET amplification. Meanwhile, high level of normalized allelic frequency of HER2 exon 18/19 indels was presented in most patients (22/25, 88%). In lung cancer, the presence of EGFR driver mutation was less common in patients with HER2 exon 18/19 indels than wild type HER2 (5% vs. 47.4%, p < 0.01). The rates of concurrent driver mutations in lung cancer were comparable between HER2 exon 18/19 indels and the two established HER2 drivers, exon 20 insertions and S310 mutations. The in vitro proliferation assay demonstrated that E698_P699insLL mutation in HER2 exon 18 and L755_E757delinsPQ mutation in HER2 exon 19 both conferred a survival advantage to Ba/F3 cells. Dose-response curves showed inhibitory effects on cell viability of several HER2 tyrosine kinase inhibitors including neratinib, lapatinib, poziotinib and afatinib. In particular, lapatinib, poziotinib and afatinib demonstrated comparable or stronger inhibitory ability toward the two HER2 mutants than wild type HER2 in terms of IC50. Conclusions: Our study revealed a novel class of HER2 KD indels in exon 18/19 that may act as driver mutations in several cancer types. The drug response observed in vitro indicated the potential to use anti- HER2 targeted therapies for HER2 exon 18/19 indels. Further studies on this rare type of HER2 mutation are warranted.


PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e68077 ◽  
Author(s):  
Ondrej Majek ◽  
Adam Gondos ◽  
Lina Jansen ◽  
Katharina Emrich ◽  
Bernd Holleczek ◽  
...  

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Ming Li ◽  
David Roder

Abstract Background Epidemiological studies have shown diabetes associated with increased risk of colorectal cancer. This study investigates the impact of a pre-cancer diabetes-related hospitalization record on colorectal cancer survival. Methods A retrospective cohort of 13190 colorectal cancer patients recorded on the South Australian Cancer Registry in 2003-2013 were examined. Diabetes-related hospitalization histories were obtained using linked inpatient data. Colorectal cancer deaths were available for 2003-2013. The association of survival from colorectal cancer with diabetes-related hospitalization history was assessed using competing risk analysis, adjusting for sociodemographic factors and cancer stage at diagnosis. Results 2765 patients with colorectal cancer (26.5%) had a history of hospital admission for diabetic complications, the most common being multiple complications (32%), followed by kidney and eye complications. The 5- and 10-year cancer survival probabilities were 63% and 56% in those with a diabetes complication history, significantly lower than 66% and 60% for patients without these complications (adjusted sub hazard ratio 1.11, 95% CI 1.02-1.20). Risk of colorectal cancer death was lower when theses diabetes-related hospitalizations were earlier than the year of cancer diagnosis - i.e., adjusted SHR 0.80, 95% CI 0.66-0.97 for 3-5 and 0.76, 95% CI 0.59-0.98 for 6+ years before the cancer diagnosis compared with same-year hospitalizations. Conclusions Colorectal cancer patients with a history of diabetes-related hospitalization have poorer survival, particularly if these hospitalizations were in the same year as the cancer diagnosis. Key messages Poorly controlled diabetes histories predict increased risk of colorectal cancer mortality.


2016 ◽  
Vol 8 (2) ◽  
Author(s):  
Yuansun Khosama ◽  
Heber B. Sapan ◽  
Jimmy Panelewen ◽  
Laurens T. B. Kalesaran

Abstract: Globally, colorectal cancer is the 4th cause of deaths. Risk factors of colorectal cancer are divided into modified and unmodified; obesity is one of the modified factors. It is accepted that insulin resistance and metabolic dysfunction act as a link between obesity and colorectal cancer. Distribution of fat tissue in Asian including Indonesian differs from that in Western people. Although of the same body mass index (BMI), Asian have higher fat tissue level than the Westerns. Body fat tissue can be measured by using BMI, waist circumference (WC), and waist-hip ratio (WHR). Acurate anthropometric measurements play some important roles in prevention of colorectal cancer. This study aimed to compare the three anthropometric parameters in colorectal cancer patients. This was a descriptive analytical study with a cross sectional design. Subjects were colorectal patients admitted to Surgery Department of Sam Ratulangi University Manado and its collaborationg hospitals from June 2015 to December 2015. There were 33 colorectal cancer patients in this study consisted of 22 males and 11 females. The ages ranged from 27 years to 77 years. The sensitivity result was as follows: BMI 33.3%, WC 51%, and WHR 42%, meanwhile the specifity result was 75.80%; 60.60%; and 60.60% respectively. The X2 test showed a P value of 0.327. Conclusion: Statistically, BMI, WC, and WHR showed no significant difference as the risk factors of colorectal cancer. However, the three parameters have to be used together to detect the accumulation of body fat tissue. It is suggested that the detection has to be applied in primary health care to diminish the colorectal cancer risk.Keywords: colorectal cancer, BMI, WC, WHRAbstrak: Kanker kolorektal (KKR) merupakan penyebab kematian keempat terbanyak di dunia. Secara garis besar faktor risiko KKR terbagi atas yang tidak dapat dimodifikasi dan yang dapat dimodifikasi, salah satunya ialah obesitas. Resistensi insulin dan disfungsi metabolik menjadi penghubung antara obesitas dan karsinoma kolorektal. Distribusi lemak tubuh pada orang Asia, termasuk Indonesia, berbeda dengan distribusi lemak tubuh pada orang Barat. Pada indeks massa tubuh (IMT) yang sama, orang Asia memiliki kadar lemak tubuh yang lebih tinggi dibandingkan orang Barat. Kadar lemak tubuh dapat dinilai melalui pengukuran IMT, lingkar pinggang (LP), dan rasio pinggang-pinggul (RPP). Penelitian ini bertujuan untuk membandingkan ketiga parameter ukuran antropometri tubuh pada pasien KKR. Penentuan patokan antropometri tubuh yang tepat membantu tindakan preventif KKR. Jenis penelitian ialah deskriptif analitik dengan desain potong lintang. Subyek penelitian ialah pasien KKR yang dirawat di Bagian Bedah Fakultas Kedokteran Universitas Sam Ratulangi Manado dan RS jejaringnya sejak bulan Juni 2015-Desember 2015. Hasil penelitian mendapatkan 33 pasien KKR (22 laki-laki dan 11 perempuan). Usia pasien berkisar 27-77 tahun. Sensitivitas IMT ialah 33,3%; LP 51%; dan RPP 42%, sedangkan spesifisitas berturut-turut ialah 75,80%; 60,60%; dan 60,60%. Uji X2 mendapatkan nilai P = 0,327. Simpulan: IMT, LP, dan RPP secara statistik tidak menunjukkan perbedaan bermakna sebagai faktor risiko KKR. Ketiganya harus diukur bersama-sama untuk mendeteksi akumulasi lemak tubuh. Disarankan deteksi harus dimulai di pelayanan primer untuk mengurangi risiko KKR.Kata kunci: KKR, IMT, LP, RPP


2020 ◽  
Vol 1 (4) ◽  
pp. 299-305
Author(s):  
Yusmaidi ◽  
Jordy Oktobiannobel ◽  
Muhammad Nur ◽  
Bella Sabila Dananda

Advances in the treatment and use of chemotherapy have been shown to improve the life expectancy rate for colorectal cancer patients. Studies conducted in China and Hongkong have shown that CapeOX combination chemotherapy regimens are more commonly used than in Europe and the United States. However, the use of chemotherapy drugs containing oxaliplatin and capecitabine can cause side effects such as hematological toxicity, which is one of them is anemia. This study aims to determine the difference in the form of a decrease in the average levels of hemoglobin and the degree of hemoglobin toxicity in colorectal cancer patients undergoing CapeOX chemotherapy. The Design in this study is a historical (retrospective) cohort. This study sample was 70 colorectal cancer patients who received CapeOX chemotherapy for 6 cycles at RSUD Dr. H. Abdul Moeloek in 2018-2019. Consecutive sampling is used in the sampling method. The statistical analysis is using Paired T-Test. There is a significant difference in the average hemoglobin level of colorectal cancer patients (p-value = <0.005), which receive CapeOX chemotherapy for 6 cycles.  Besides, there is an increase in the number of patients who get hemoglobin toxicity and the chemotherapy cycle. In the first cycle, 59 patients (84.3%) got hemoglobin toxicity after chemotherapy, and the number continued to increase to 69 patients (98.6%) in the sixth cycle. There was a decrease in hemoglobin levels in colorectal cancer patients who received CapeOX chemotherapy with p-value = <0.05 and increased patients who got hemoglobin toxicity.


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