Purpose: Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC). Experimental Design: Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board. Results: A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response. Conclusions: The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.

Purpose Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in China and the 5-year mortality rate is up to 70%. Studies on the ESCC genetic landscape are needed to further explore clinical therapeutic strategies. In this study, we evaluated the genetic landscape of ESCC to aid the search for clinical therapeutic strategies. Patients and Methods A total of 225 ESCC patients were enrolled in this study. Deep sequencing of 450 cancer genes was performed on formalin-fixed paraffin-embedded tumor biopsies and matched blood samples from patients. Tumor mutational burden (TMB) was calculated using an algorithm developed in-house. Results Our results showed that the most commonly mutated genes in ESCC were TP53 (96%), CCND1 (46%), FGF4 (44%), FGF19 (44%), FGF3 (44%), CDKN2A (31%), PIK3CA (26%), NOTCH1 (24%), KMT2D (18%), FAT1 (16%), and LRP1B (16%). We found that TMB correlated with patient drinking status. We identified mutations associated with sex, early ESCC, high TMB, and metastasis lymph nodes. KMT2D mutations associated with sex ( P = 0.035), tumor stage ( P = 0.016), high TMB ( P = 0.0072), and overall survival of patients ( P = 0.0026). SPEN mutations associated with high TMB ( P = 0.0016) and metastasis-positive lymph nodes ( P = 0.027). These results suggested that SPEN and KMT2D could be potential prognosis biomarkers for Chinese patients with ESCC. We also found that the number of positive lymph nodes was associated with disease-free survival. Clinical target gene analysis indicated that nearly half of Chinese ESCC patients might benefit from treatment with gene-specific target drugs. Conclusion Our study revealed the ESCC mutational landscape in 225 Chinese patients and uncovered the potential prognosis biomarker for Chinese patients with ESCC.

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Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide.Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified.Methods: A total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27-78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high.Results: A total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0-28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A, and FGF19. SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III-IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 μmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III-IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 μmg/L) (P=0.009, OR =3.414). Conclusions:The most frequently mutated genes of HCC patients in China were TP53, TERT, and CTNNB1, which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III-IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I-II grade,

Background: Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy, with limited adjuvant therapy. The present study aims to explore the actionable alterations and precision oncology for GBC patients.Methods: Patients with pathologically confirmed GBC who progressed after first-line systemic treatment were enrolled. Genomic alterations were captured by ultra-deep targeted next-generation sequencing (tNGS).The actionabilities of alterations and the therapeutic regimens were evaluated by a multidisciplinary tumor board (MDTB).Results: Sixty patients with GBC were enrolled and analyzed. tNGS was successfully achieved in all patients. The median tumor mutation burden for GBC patients was 5.4 (range: 0.8-36.74) mutations/Mb, and the most common mutations were in TP53 (73%), CDKN2A (25%) and PIK3CA (20%). The most frequently copy-number altered genes were CDKN2A deletion (11.7%) and ERBB2 amplification (13.3%).23% of the patients displayed gene fusion; 17 fusion events were identified, and 14 of the 17 fusion events co-occurred with mutations in driver genes. In total, 46 of the 60 (76%) patients were identified as possessing at least one actionable target to proceed precision oncology. Conclusions:The present study revealed the mutational profile for the clinical practice of precision oncology in GBC patients.