人乳头瘤病毒阳性与阴性食管腺癌的基因组分析确定了不同的突变格局。

Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape.

作者信息

Rajendra Shanmugarajah, Wang Bin, Merrett Neil, Sharma Prateek, Humphris Jeremy, Lee Hong Ching, Wu Jianmin

机构信息

Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia.

出版信息

J Med Genet. 2016 Apr;53(4):227-31. doi: 10.1136/jmedgenet-2015-103411. Epub 2015 Oct 15.

DOI:10.1136/jmedgenet-2015-103411

PMID:26470716

Abstract

BACKGROUND

High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). We therefore hypothesised that HPV associated OAC may have distinct genomic aberrations compared with viral negative oesophageal cancer.

METHODS

Whole exome sequencing was performed to explore the mutational landscape and potential molecular signature of HPV-positive versus HPV-negative OAC. Four hr-HPV-positive and 8 HPV-negative treatment-naive fresh-frozen OAC tissue specimens and matched normal tissue were analysed to identify somatic genomic mutations. Data were subjected to cancer driver gene identification and pathway analysis.

RESULTS

The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative patients with oesophageal cancer (1.31 mutations/Mb vs 2.56 mutations/Mb, p=0.048). TP53 aberrations were absent in the HPV-positive OAC group whereas 50% of the HPV-negative patients with OAC exhibited TP53 mutations. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at adenine-adenine (AA) dinucleotide was observed in 5/7 Siewert class I OAC samples but none (0/5) in Siewert class II tumours (p=0.027).

CONCLUSIONS

These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OACs indicating different biological mechanisms of tumour formation.

摘要

背景

高危型人乳头瘤病毒（hr-HPV）与一部分食管腺癌（OAC）患者有关。因此，我们推测与HPV相关的OAC与病毒阴性的食管癌相比可能具有不同的基因组畸变。

方法

进行全外显子组测序以探索HPV阳性与HPV阴性OAC的突变情况及潜在分子特征。分析了4例hr-HPV阳性和8例HPV阴性的未经治疗的新鲜冷冻OAC组织标本及匹配的正常组织，以鉴定体细胞基因组突变。对数据进行癌症驱动基因鉴定和通路分析。

结果

HPV阳性组的非沉默体细胞突变比病毒阴性的食管癌患者少约50%（1.31个突变/Mb对2.56个突变/Mb，p=0.048）。HPV阳性的OAC组未出现TP53畸变，而50%的HPV阴性OAC患者存在TP53突变。HPV阴性的癌症在癌症驱动基因中富含非沉默突变，但HPV阳性肿瘤并非如此。在5/7例Siewert I型OAC样本中观察到腺嘌呤-腺嘌呤（AA）二核苷酸处的A>C颠换富集，但在Siewert II型肿瘤中无此现象（0/5，p=0.027）。