The genetic landscape of endometrial clear cell carcinomas

Abstract

Clear cell carcinoma of the endometrium is a rare type of endometrial cancer generally associated with an aggressive clinical behavior. Here we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs) and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs displayed abnormal expression patterns of p53, ARID1A and at least one DNA mismatch repair protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, which revealed that two ECCs (7%) were ultramutated and harbored mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations, and 18% and 11% harbored CCNE1 and ERBB2 amplifications, respectively, while 11% showed DAXX homozygous deletions. In comparison to non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA), ECCs less frequently harbored mutations affecting CTNNB1 and PTEN but more frequently PPP2R1A and TP53 mutations. Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harbored TP53 mutations. Using a surrogate model for the molecular-based TCGA classification, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs are a histologically and genetically heterogeneous group of tumors with varying outcomes. Furthermore, our data suggest that the classification of ECCs as being generally “high-grade” or “type II” tumors may not be warranted.

HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in‐situ hybridisation

“…Response to traditional treatment with surgery, radiotherapy or chemotherapy is poorer than other high‐grade carcinomas . Molecular alterations in CCC are being identified, and strategies with targeted therapies are still in development . The current concept of precision cancer medicine strives for a patient tailored approach.…”

Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

“…MSK‐IMPACT sequencing data were analysed as previously described . In brief, paired‐end reads were aligned to the human reference genome GRCh37 using the burrows – wheeler aligner (0.7.15) .…”

“…Variants with a mutant allelic fraction (MAF) of <1% and/or variants supported by fewer than five reads and/or covered by fewer than 10 reads at a given locus were discarded. Additionally, variants whose MAF in the tumour was less than five times that in the matched normal sample were disregarded, as were variants that were present at >5% minor allele frequency in dbSNP (Build 137) and in ExAC (0.3.1) . Mpileup files generated from samtools mpileup (1.2.1) for each sample were used to determine whether a given mutation detected existed in the BAM file of the corresponding matched SBT, LGSC, HGSC or PDC from the same individual.…”

“…Copy number alterations and loss of heterozygosity (LOH) were identified with facets as previously described . The cancer cell fraction (CCF) for each mutation was inferred with absolute (1.0.6) as previously described .…”

“…Copy number alterations and loss of heterozygosity (LOH) were identified with facets as previously described . The cancer cell fraction (CCF) for each mutation was inferred with absolute (1.0.6) as previously described . Mutations for which the probability of being clonal was >50% or those for which the lower bound of the 95% confidence interval of the CCF was >90% were classified as clonal .…”