Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva

Authors

Mi-Ryung Han

Sun Shin

Hyeon-Chun Park

Min Sung Kim

Sung Hak Lee

Seung Hyun Jung

Sang Yong Song

Sug Hyung Lee

Yeun-Jun Chung

Doi

10.1038/emm.2017.265

PMID: 29422544 · DOI: 10.1038/emm.2017.265 · Journal: Experimental & Molecular Medicine (2018)

TL;DR

Han et al. performed whole-exome sequencing and copy-number profiling on 15 Korean vulvar squamous cell carcinomas (6 HPV-positive, 9 HPV-negative) — the first genome-wide characterization of this tumor type. HPV(−) tumors recapitulated the classical vulvar SCC mutation pattern (TP53, CDKN2A, HRAS) plus 7p and 8q gains and 2q loss, while HPV(+) tumors carried novel-for-vulvar-SCC mutations in PIK3CA, BRCA2, and FBXW7. HPV(−) cases had a higher mutational load than HPV(+) cases, but copy-number burden and mutational signatures did not differ between the two etiologic groups. Notably, PIK3CA and FAT1 alterations each occurred in 40% (6/15) of cases, kataegis was found in 2 HPV(+) tumors, and copy-neutral loss of heterozygosity in 4 tumors (1 HPV(+), 3 HPV(−)).

Cohort & data

  • 15 Korean vulvar SCC patients (ages 45–83) with surgically resected primary tumors and matched normal tissue, profiled by whole-exome sequencing and copy-number analysis (PMID:29422544).
  • HPV status by real-time PCR (Seegene): 6 HPV(+) (HPV16, 52, or 58 — all high-risk) and 9 HPV(−) (PMID:29422544).
  • Tissue: 1 frozen (VSCC2), 14 FFPE; tumor cell purity ~70% after microdissection by two pathologists (PMID:29422544).
  • Cancer type: vulvar squamous cell carcinoma (VSC).
  • Dataset: vsc_cuk_2018 (The Catholic University of Korea, 2018).
  • Library prep: Agilent SureSelect Human All Exome V4; alignment by BWA v0.7.15 to hg19; Picard v2.7.1 and Samtools v1.3.1 for de-duplication; GATK v3.6 for local realignment and BQSR (PMID:29422544).
  • Variant calling: MuTect for SNVs and SomaticIndelDetector for indels; ANNOVAR for functional annotation; PolyPhen-2 for missense impact prediction; 21 mutations across 9 genes validated by digital PCR or Sanger sequencing (PMID:29422544).
  • Mutational signatures by the SomaticSignatures R package using NMF, compared to 30 COSMIC signatures (cosine similarity) and to TCGA SCCs (CESC, ESCA, HNSC, LUSC) plus published CSCC and oral SCC datasets (PMID:29422544).
  • Copy-number alterations called via the ngCGH module and RankSegmentation in Nexus v7.5; LOH events inferred with Sequenza, then manually curated using depth ratio and B-allele frequency (PMID:29422544).

Key findings

  • Etiology-stratified mutation burden: HPV(−) vulvar SCCs carried more nonsilent mutations and more driver mutations than HPV(+) cases, while CNA burden and mutational signatures did not differ between the two groups (PMID:29422544).
  • HPV(−) drivers recapitulate prior reports: known recurrent mutations in TP53, CDKN2A, and HRAS (PMID:29422544).
  • Recurrent CNAs in HPV(−): 7p and 8q gains and 2q loss (PMID:29422544).
  • Novel HPV(+) mutations for vulvar SCC: PIK3CA, BRCA2, and FBXW7 — none previously reported in this tumor type (PMID:29422544).
  • High-frequency alterations across the cohort: PIK3CA altered in 40% (6/15) and FAT1 altered in 40% (6/15) of vulvar SCCs irrespective of HPV status (PMID:29422544).
  • Kataegis (localized hypermutation with average inter-mutation distance ≤10 kb) detected in 2 HPV(+) tumors (PMID:29422544).
  • Copy-neutral loss of heterozygosity observed in 4 tumors (1 HPV(+), 3 HPV(−)) (PMID:29422544).
  • The authors compared their mutation signatures against the 30 COSMIC signatures and four TCGA SCC cohorts (CESC, ESCA, HNSC, LUSC) plus skin and oral SCC datasets (PMID:29422544).
  • Prior targeted-panel work (cited by the authors) had reported that 83% of HPV(−) vulvar SCCs carried somatic mutations in TP53, CDKN2A, HRAS, KRAS, PIK3CA, PPP2R1A, or PTEN, versus only 17% of HPV(+) cases having a TP53 mutation — context this study extends to whole-exome scope (PMID:29422544).

Genes & alterations

  • TP53 — somatic mutations in HPV(−) vulvar SCCs; consistent with prior literature naming TP53 the most commonly mutated gene in HPV(−) vulvar SCC (PMID:29422544).
  • CDKN2A — recurrent in HPV(−) tumors (PMID:29422544).
  • HRAS — recurrent in HPV(−) tumors (PMID:29422544).
  • PIK3CA — first description in HPV(+) vulvar SCC; altered in 40% of the 15-tumor cohort overall (PMID:29422544).
  • BRCA2 — novel mutation finding in HPV(+) vulvar SCC (PMID:29422544).
  • FBXW7 — novel mutation finding in HPV(+) vulvar SCC (PMID:29422544).
  • FAT1 — altered in 40% of vulvar SCCs irrespective of HPV status (PMID:29422544).
  • KRAS, PTEN, PPP2R1A — referenced from prior targeted-panel literature on HPV(−) vulvar SCC; not specifically called out as new findings in this WES cohort (PMID:29422544).

Clinical implications

  • The authors frame the work as foundational for “the development of clinical treatment strategies” rather than asserting any specific therapeutic recommendation (PMID:29422544).
  • The 40% prevalence of PIK3CA alterations across both etiologic subgroups suggests PI3K-pathway inhibition may be a tractable hypothesis worth testing in vulvar SCC, though the paper itself does not name a specific drug or trial.
  • ~33% of vulvar SCC patients recur with limited therapeutic options (cited by the authors as motivation), underscoring the unmet need this molecular characterization aims to inform (PMID:29422544).

Limitations & open questions

  • Small cohort. N=15 (6 HPV(+), 9 HPV(−)) limits statistical power to detect rarer drivers and to claim subgroup-specific signature differences as truly absent.
  • Single-institution, single-ethnicity cohort. All patients were Korean and accrued through The Catholic University of Korea — generalizability to other populations is untested.
  • FFPE-dominant material. 14 of 15 tumors were FFPE, which can introduce sequencing artifacts (notably C>T deamination) that may confound mutation-signature interpretation.
  • No survival or treatment-response data linked to the molecular calls in the analyzed text.
  • Open question for cross-paper synthesis: whether the high PIK3CA and FAT1 prevalence reported here replicates in larger vulvar SCC cohorts and aligns with rates seen in other gynecologic and head-and-neck SCCs (CESC, HNSC).

Citations from this paper used in the wiki

  • “we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (−) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (−) SCCs.” (Abstract)
  • “In HPV (+), we found novel mutations in PIK3CA, BRCA2 and FBXW7 that had not been reported in vulvar SCCs.” (Abstract)
  • “HPV (−) SCCs exhibited more mutational loads (numbers of nonsilent mutations and driver mutations) than HPV (+) SCCs, but the CNA loads and mutation signatures between HPV (+) and HPV (−) SCCs did not differ.” (Abstract)
  • “40% and 40% of the 15 vulvar SCCs harbored PIK3CA and FAT1 alterations, respectively.” (Abstract)
  • “the SCCs harbored kataegis (a localized hypermutation) in 2 HPV (+) SCCs and copy-neutral losses of heterozygosity in 4 (one HPV (+) and 3 HPV (−)) SCCs.” (Abstract)
  • “Approximately one-third of all vulvar SCC patients suffer from recurrence, for which therapeutic options are limited.” (Introduction)
  • “a recent study identified that most HPV-negative (−) vulvar SCCs (83%) contained one or more somatic mutations in TP53, CDKN2A, HRAS, KRAS, PIK3CA, PPP2R1A and PTEN, with TP53 being the most commonly mutated gene.” (Introduction)
  • “HPV-positive (+) vulvar SCCs harbored a TP53 mutation in 17% of cases but the remaining 83% were silent without any driver mutations.” (Introduction)
  • “Putative regions of kataegis were identified in samples where mutations had an average inter-mutation distance of no more than 10 kb.” (Methods)

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