Stachler Matthew D, Rinehart Elizabeth M, Garcia Elizabeth, Lindeman Neal I
Department of Pathology, Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA.
Appl Immunohistochem Mol Morphol. 2016 May-Jun;24(5):313-9. doi: 10.1097/PAI.0000000000000195.
Genotyping clinical cancer specimens determines a fuller spectrum of mutations that an individual tumor harbors, and thus provides better insight into its molecular pathogenesis. Using genotyping data collected during routine clinical care our objective was to better determine the genomic landscape associated with PIK3CA mutations since much interest has been placed on PIK3CA targeted therapy.
We performed multiplexed tumor genotyping within our CLIA-certified clinical laboratory on all consenting cancer patients who presented to the Brigham and Women's Hospital/Dana-Farber Cancer Center, regardless of histologic subtype. A total of 3252 cancers were genotyped for 471 mutations in 41 cancer-associated genes (including 23 mutations in PIK3CA), using a PCR-mass spectrometry assay.
A total of 288 (9%) samples contained a mutation in PIK3CA, involving 25 different primary sites. In 117 (41%) cases, the PIK3CA mutation was found with at least 1 other mutation, many known oncogenic drivers, while only 7% of the non-PIK3CA mutated cases, when comparing like tumor types, had >1 mutation (P<0.0001). Breast cancers had the highest rate of PIK3CA mutations (34%), which correlated with estrogen receptor + status (P=0.0002).
These findings suggest that PIK3CA mutations may be a relatively late event and may function primarily in a supporting/modifying role, and not as a primary driver of oncogenesis. Although further studies are needed, our observations during clinical tumor genotyping suggest that when other pro-oncogenic pathways are mutated along with PIK3CA, then, PIK3CA inhibition alone may not be effective and combination therapy may be warranted.
对临床癌症标本进行基因分型可确定个体肿瘤所携带的更全面的突变谱，从而更好地洞察其分子发病机制。鉴于PIK3CA靶向治疗备受关注，我们利用常规临床护理期间收集的基因分型数据，旨在更好地确定与PIK3CA突变相关的基因组格局。
我们在获得CLIA认证的临床实验室中，对所有同意参与的、前往布莱根妇女医院/达纳-法伯癌症中心就诊的癌症患者进行多重肿瘤基因分型，无论其组织学亚型如何。使用聚合酶链反应-质谱分析法，对3252例癌症进行了41个癌症相关基因中471个突变的基因分型（包括PIK3CA中的23个突变）。
共有288份（9%）样本含有PIK3CA突变，涉及25个不同的原发部位。在117例（41%）病例中，发现PIK3CA突变的同时至少还存在1个其他突变，其中许多是已知的致癌驱动因素，而在比较相同肿瘤类型时，非PIK3CA突变病例中只有7%有>1个突变（P<0.0001）。乳腺癌的PIK3CA突变率最高（34%），这与雌激素受体阳性状态相关（P=0.0002）。
这些发现表明，PIK3CA突变可能是一个相对较晚发生的事件，其主要功能可能是支持/修饰作用，而非肿瘤发生的主要驱动因素。尽管还需要进一步研究，但我们在临床肿瘤基因分型过程中的观察结果表明，当其他促癌途径与PIK3CA同时发生突变时，仅抑制PIK3CA可能无效，可能需要联合治疗。
