BLM mutation is associated with increased tumor mutation burden and improved survival after immunotherapy across multiple cancers

Abstract

Background: BLM encodes a RecQ DNA helicase that regulates genomic stability, and its mutations are associated with increased cancer susceptibility. Here, we show a multifaceted role of BLM mutations in tumorigenesis and immunotherapy.

Methods and results: A total of 10,967 cancer samples from the cancer genome atlas database were analyzed, 1.6% of which harbored BLM somatic mutations. BLM mutation was found to be associated with increased tumor mutation burden and more immune-active tumor microenvironment in these patients. Moreover, clinical data of 2785 patients from nine immunotherapy studies were analyzed to study BLM mutations' impact on immunotherapy. Among them, 69 patients harbored BLM mutations, and interestingly, they had significantly higher survival probability than patients without BLM mutations. Cancer patients with BLM mutations had higher complete response and partial response rates, but lower progressive disease rate than BLM nonmutant patients.

Conclusion: Our study shows that BLM mutation is related to improved survival after immunotherapy across multiple cancers.

Keywords: BLM mutation; immunotherapy; survival; tumor mutation burden.

FIGURE 1

BLM mutation spectrum in multiple cancer types and its association with tumor immune landscape. (A) Comparison of BLM expression levels between cancer patients and healthy controls. Data were presented as median with its interquartile range. (B) BLM alteration frequency in multiple TCGA cancer types. (C) Distribution of multiple types of BLM mutations. (D) The co‐altered genes in BLM altered cancer patients. (E) The infiltration of multiple immune cells in cancer patients with or without BLM mutation. (F) Overall survival and disease‐free survival of TCGA cancer patients with or without BLM alteration. ACC: adrenocortical carcinoma; BLCA: bladder urothelial carcinoma; BRCA: breast invasive carcinoma; CESC: cervical squamous cell carcinoma; CHOL: cholangiocarcinoma; COAD: colon adenocarcinoma; DLBC: diffuse large B cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: brain lower grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; MESO: mesothelioma; OV: ovarian serous cystadenocarcinoma; PAAD: pancreatic adenocarcinoma; PCPG: pheochromocytoma and paraganglioma; PRAD: prostate adenocarcinoma; READ: rectum adenocarcinoma; SARC: sarcoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UCS: uterine carcinosarcoma; UVM: uveal melanoma.

FIGURE 2

The association of BLM mutation with tumor mutation burden (TMB) and survival after immunotherapy. (A) Comparisons of mutation count, altered genome fraction, TMB, microsatellite instability (MSI) sensor score and MSI Microsatellite Analysis for Normal‐Tumor InStability (MANTIS) score in BLM altered group and unaltered group. Data were presented as median with its interquartile range. (B) Comparisons of TMB, MSIsensor score and MSI MANTIS score in BLM nonmutant patients and patients with BLM missense, truncating or multiple mutations. Data were presented as median with its interquartile range. (C) Survival outcome of BLM mutant and nonmutant cancer patients treated with immune checkpoint inhibitors in the nine studies. (D) Fractions of immunotherapy‐treated cancer patient response as classified by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease). (E) Comparisons of TMB and mutation count in BLM mutant and nonmutant cancer patients from a multi‐cancer cohort (study 1). Data were presented as median with its interquartile range. (F) Top co‐altered genes in BLM mutant cancer patients from a multi‐cancer cohort (study 1).