Melanoma genome sequencing reveals frequent PREX2 mutations

Authors

Berger MF

Hodis E

Heffernan TP

Deribe YL

Lawrence MS

Protopopov A

Ivanova E

Watson IR

Nickerson E

Ghosh P

Zhang H

Zeid R

Ren X

Cibulskis K

Sivachenko AY

Wagle N

Sucker A

Sougnez C

Onofrio R

Ambrogio L

Auclair D

Fennell T

Carter SL

Drier Y

Stojanov P

Singer MA

Voet D

Jing R

Saksena G

Barretina J

Ramos AH

Pugh TJ

Stransky N

Parkin M

Winckler W

Mahan S

Ardlie K

Baldwin J

Wargo J

Schadendorf D

Meyerson M

Gabriel SB

Golub TR

Wagner SN

Lander ES

Getz G

Chin L

Garraway LA

Doi

10.1038/nature11071

PMID: 22622578 · DOI: 10.1038/nature11071 · Journal: Nature (2012)

TL;DR

Berger et al. performed whole-genome sequencing of 25 metastatic melanomas and matched germline DNA, revealing a wide range of somatic mutation rates correlated with UV exposure history (3-111 mutations per Mb). The study identified PREX2 – a PTEN-interacting protein – as a significantly mutated gene in melanoma, with ~14% non-synonymous mutation frequency in an independent extension cohort of 107 melanomas. Functional experiments demonstrated that ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo.

Cohort & data

  • Discovery cohort: 25 metastatic melanomas with matched germline DNA, sequenced by whole-genome sequencing (59-fold tumor / 32-fold normal haploid coverage).
  • Extension cohort: 107 tumor/normal pairs (45 tumors + 62 short-term cultures) from multiple institutions, screened by bidirectional capillary (Sanger) sequencing of 40 PREX2 exons.
  • Cancer type: Cutaneous melanoma (SKCM), including 2 acral subtype melanomas and 23 trunk/non-acral melanomas.
  • Dataset: skcm_broad_dfarber.
  • Sequencing: Illumina GAIIx (5 cases) and Illumina HiSeq 2000 (20 cases); paired-end 101-nt reads aligned to hg19 with BWA.
  • Data availability: dbGaP accession phs000452.v1.p1.

Key findings

  • Somatic mutation rates varied nearly 100-fold across 25 melanomas: acral melanomas had the lowest rates (3 and 14 mutations/Mb), trunk melanomas were intermediate (5-55/Mb), and a chronically sun-exposed melanoma had the highest (111/Mb) (PMID:22622578).
  • C>T transitions consistent with UV mutagenesis dominated high-mutation-rate tumors (93% in the hypermutated ME009 sample vs. 36% in acral ME015) (PMID:22622578).
  • BRAF V600E was present in 16/25 tumors (64%) and NRAS was mutated in 9/25 (36%), in a mutually exclusive pattern (PMID:22622578).
  • 11 genes were significantly mutated (q < 0.01); PREX2 ranked among the top significant genes, with 11/25 tumors harboring at least 1 non-synonymous PREX2 mutation in the discovery cohort (PMID:22622578).
  • In the 107-sample extension cohort, PREX2 had a 14% non-synonymous mutation frequency (15 non-synonymous changes out of 24 total mutations) (PMID:22622578).
  • An average of 97 structural rearrangements per genome was detected (range: 6-420), with evidence of chromothripsis in select tumors (PMID:22622578).
  • Recurrently rearranged genes included PTEN (4 tumors), MAGI2 (3 tumors), FHIT (6 tumors), MACROD2 (5 tumors), CSMD1 (4 tumors), and RBFOX1 (4 tumors) (PMID:22622578).
  • Acral melanoma ME032 harbored 314 rearrangements but a low point mutation rate, suggesting alternative genomic alteration mechanisms (PMID:22622578).
  • Ectopic expression of 3 truncated PREX2 variants and the G844D point mutant significantly accelerated in vivo tumor formation in PMEL-NRAS* melanocytes transplanted into immunodeficient mice, compared to wild-type PREX2 or GFP controls (PMID:22622578).

Genes & alterations

  • PREX2: Significantly mutated in melanoma; 11/25 discovery tumors with non-synonymous mutations (including 4 nonsense truncations), 14% frequency in 107-sample extension cohort. Also subject to complex rearrangements and amplification in acral melanoma ME032. Mutant PREX2 gains oncogenic activity in melanocytes (PMID:22622578).
  • BRAF: V600E hotspot mutation in 16/25 (64%) melanomas. Most significantly mutated gene in the cohort (PMID:22622578).
  • NRAS: Mutated in 9/25 (36%) melanomas, mutually exclusive with BRAF except for one non-canonical T50I substitution in hypermutated ME009 (PMID:22622578).
  • PTEN: Recurrently disrupted by structural rearrangements in 4/25 tumors. PREX2 is a known PTEN-interacting protein and negative regulator of PTEN (PMID:22622578).
  • KIT: 21-bp in-frame deletion in exon 11 detected in acral melanoma ME032 (PMID:22622578).
  • ETV1: Complex rearrangements (6 validated, including 4 interchromosomal translocations) and high-level amplification in acral melanoma ME032. Known melanoma oncogene associated with MITF upregulation (PMID:22622578).
  • MITF: Referenced as melanocyte master transcriptional regulator and lineage survival oncogene, linked to ETV1 dysregulation (PMID:22622578).
  • MAGI2: Recurrently rearranged in 3/25 tumors; encodes a PTEN-binding and stabilizing protein (PMID:22622578).

Clinical implications

  • BRAF V600E mutations predict sensitivity to selective RAF inhibitors (e.g., vemurafenib), the first effective targeted therapy for metastatic melanoma, though acquired resistance emerges rapidly (PMID:22622578).
  • KIT exon 11 mutations in acral melanoma may confer sensitivity to imatinib, consistent with prior reports of marked clinical responses (PMID:22622578).
  • PREX2 mutations represent a novel, recurrent genomic event in melanoma that may serve as a future therapeutic target or biomarker, though no therapeutic agents targeting PREX2 are currently available (PMID:22622578).

Limitations & open questions

  • The discovery cohort of 25 samples is small, limiting power to detect rare significantly mutated genes beyond PREX2.
  • The precise oncogenic mechanism of PREX2 mutations remains unclear – mutations are distributed across the gene (not confined to hotspots), and the paper notes they may act through dominant-negative effects or subtle dysregulation rather than classic gain-of-function or loss-of-function.
  • Short-term cultures in the extension cohort showed a different non-synonymous:synonymous ratio (55% vs. 100% in tumors), raising questions about whether in vitro selection pressures differ from in vivo.
  • Functional validation was performed in NRAS-mutant melanocyte backgrounds only; relevance to BRAF-mutant or wild-type contexts is unexplored.
  • The study predates modern immunotherapy and does not address the relationship between UV mutation burden and immunotherapy response, which is now a major clinical question.

Citations from this paper used in the wiki

  • “A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-UV exposed hairless skin of the extremities (3 and 14 per Mb genome), intermediate in those originating from hair-bearing skin of the trunk (range = 5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb).” (Abstract)
  • “PREX2 - a PTEN-interacting protein and negative regulator of PTEN in breast cancer - as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas.” (Abstract)
  • “PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo.” (Abstract)
  • “The BRAFV600E mutation was present in 16 of 25 tumors (64%)… NRAS was mutated in 9 of 25 tumors (36%) in a mutually exclusive fashion with BRAF.” (Results)
  • “We identified an average of 97 structural rearrangements per melanoma genome (range: 6-420).” (Results)

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