11q13.2

C11orf23,PP6R3,SAP190,SAPL,SAPLa,SAPS3

PPP6R3 is involved in many and heterogeneous genomic translocations in different kind of tumors (Table. 3) and it has been proposed that this happens because it possess a potent promotor activity (Guo et al., 2016).

Name	5 end	3 end	Loc1	Loc2	Description	Type	Disease	Organ	Code	Ref.
RNF121/PPP6R3	RNF121	PPP6R3	11q13.4	11q13.2	t(11;11)(q13;q13)	Fusion gene	Adenocarcinoma	Breast	BRCA	Yoshihara et al., 2015
VPS50/PPP6R3	VPS50	PPP6R3	7q21.3	11q13.2	t(7;11)(q21;q13)	Translocation	(?)	(?)	(?)	-

 Chronic myeloid leukemiaBloodCMLStopera et al., 1990 TNFRSF21/PPP6R3TNFRSF21PPP6R3 6p12.3 11q13.2t(6;11)(p12;q13)TranslocationAdenocarcinomaBreastBRCABanerji et al., 2012 PPP6R3/YAP1PPP6R3YAP111q13.211q22.1 t(11;11)(q13;q22)Fusion gene Transitional cell carcinomaBladderBLCAYoshihara et al., 2015 PPP6R3/EIF4G3PPP6R3EIF4G311q13.2 1p36.12t(1;11)(p36;q13)TranslocationMalignant melanomaSkinSKCM- NADSYN1/PPP6R3NADSYN1PPP6R3 11q13.411q13.2t(11;11)(q13;q13)Fusion geneMalignant melanomaSkinSKCMHu et al., 2018; Klijn et al., 2015 PPP6R3/MTL5PPP6R3MTL511q13.211q13.3 t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015 PPP6R3/INTS4 PPP6R3INTS4 11q13.2 11q14.1t(11;11)(q13;q14) Fusion geneAcute lymphoblastic leukemia/lymphoblastic lymphoma (T-Lineage)BloodT-ALLLiu et al., 2017 PPP6R3/SSH2PPP6R3SSH211q13.217q11.2t(11;17)(q13;q11)TranslocationAdenocarcinomaBreastBRCAYoshihara et al., 2015 TMPRSS6/PPP6R3TMPRSS6PPP6R3 22q12.311q13.2t(11;22)(q13;q12)TranslocationLiver hepatocellular carcinomaLiver LIHC- PPP6R3/USP6 PPP6R3USP6 11q13.2 17p13.2 t(11;17)(q13;p13) TranslocationNodular fasciitisSoft tissueNFGuo et al., 2016 Multiple myelomaBloodMMSawyer et al., 1995; Sawyer et al., 2014 Table.3 PPP6R3 rearrangements: translocations and fusion genes (reworked from ps://www.ncbi.nlm.nih.gov/homologene; http://www.tumorfusions.org; https://cgap.nci.nih.gov/Chromosomes; http://quiver.archerdx.com)
[ (?) ] unknown; [ - ] no reference

Acute lymphoblastic leukemia (ALL)

The fusion gene PPP6R3/ INTS4 has been found in T-ALL (Liu et al., 2017), while a t(11;17)(q13;q11) PPP6R3/ SSH2 was discovered in a childhood T/BCP (T/ B-cell precursor) ALL (Schmiegelow et al., 2012).

Bladder cancer

The fusion genes PPP6R3/ SHANK2 and PPP6R3/ YAP1 have been found in transitional cell carcinoma of the bladder (Hu et al., 2018; Yoshihara et al., 2015; http://www.tumorfusions.org).

Breast cancer

Many fusion genes and abnormal translocation was discovered. C11orf80 /PPP6R3, KDM2A/PPP6R3, PC/PPP6R3, PPP6R3/ FADD, PPP6R3/ MTL5, PPP6R3/ POLD3, PPP6R3/ SPTBN2, t(11;17)(q13;q11) PPP6R3/SSH2, RNF121/PPP6R3, t(11;14)(q13;q12) STRN3/PPP6R3 and t(6;11)(p12;q13) TNFRSF21/PPP6R3 have been found in breast adenocarcinoma (Hu et al., 2018; Yoshihara et al., 2015; http://www.tumorfusions.org)

Cervical carcinoma

A t(11;15)(q13;q22) RAB11A/PPP6R3 has been found in cervical carcinoma (http://www.tumorfusions.org).

Gastric cancer

The fusion gene PPP6R3/ RHOD has been found in gastric adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)

t(11;17)(q13;p13)PPP6R3/USP6 in hematological malignancies.

A t(11;17)(q13;p13)PPP6R3/ USP6 has been found in Hairy cell leukemia, Multiple myeloma, and Chronic myeloid leukemia (Sawyer et al., 2014 ; Sawyer et al., 1995 ; Nacheva et al., 1992; Stopera et al., 1990 http://www.tumorfusions.org)

Hepatocellular carcinoma

A t(11;22)(q13;q12) TMPRSS6/PPP6R3 has been found in hepatocellular carcinoma (http://www.tumorfusions.org).

Lung squamous cell carcinoma

In squamous cell carcinoma of the lung was discovered the fusion gene EEF1G/PPP6R3 (Hammerman et al., 2012). Other detected are: a t(7;11)(q21;q13) CCDC132/PPP6R3, PPP6R3/ ARHGAP1 fusion gene, PPP6R3/ CNTN5 fusion gene, PPP6R3/ LRP5 fusion gene, a t(7;11)(q13;q34)PPP6R3/ MGAM and a t(7;11)(q34;q13) SSBP1/PPP6R3 (Yoshihara et al., 2015; Hammerman et al., 2012; http://www.tumorfusions.org)
In squamous cell carcinoma of the lung was found the presence of the fusion gene 5 EEF1G- 3 PPP6R3 deriving by the genomic translocation and fusion of a part of EEF1G gene with a portion of PPP6R3 gene, both located on chromosome 11 (Hammerman et al., 2012).

Malignant melanoma

The fusion genes CTTN/PPP6R3, NADSYN1/PPP6R3 and PPP6R3/ ACER3 have been found in malignant melanoma. In addition, a t(1;11)( p36;q13) PPP6R3/ EIF4G3 has also been found (Hu et al., 2018; Klijn et al., 2015; http://www.tumorfusions.org)

Malignant Nodular Fasciitis

Nodular fasciitis (NF) occurs in subcutaneous tissue and it is generally a benign self-limiting myofibroblastic proliferation (Bernstein and Lattes, 1982). Sometimes was found USP6 gene rearrangements (Erickson-Johnson et al., 2011) and surprendently in one case was revealed the presence of PPP6R3/USP6 fusion gene with both genomic amplification and overexpression (Guo et al., 2016) that could explain the more aggressive behavior seen in malignant NF case report.

It was described the fusion gene 5 PPP6R3 / 3 USP6 deriving by the genomic translocation and fusion of a part of PPP6R3 gene, situated on chromosome 11, with a portion of USP6 gene, instead located on chromosome 17. In particular, the breakpoint reside at the end of exon 1 of PPP6R3 (non-coding) and 155 bp upstream of coding sequence of USP6 gene (Guo et al., 2016).

The presence of the novel PPP6R3/USP6 fusion gene was linked to the increase of malignancy of the nodular faciitis (NF). Other tumors were tested for the presence of this chimeric gene, such as aggressive angiomyxoma , malignant peripheral nerve sheath tumor, dermatofibroma/ benign fibrous histiocytoma and melanoma. In that cases the results were negatives (Guo et al., 2016). Some authors detect PPP6R3/USP6 in hairy cell leukemia, multiple myeloma and chronic myeloid leukemia (Sawyer et al., 2014; Sawyer et al., 1995; Nacheva et al., 1992 ; Stopera et al., 1990).

Nervous system tumors

Malignant peripheral nerve sheath tumors (MPNSTs), also called neurofibrosarcomas, are a rare aggressive, metastatic, nerve-associated cancer type. It was found that in about 10% of this malignancy there are mutations on PPP6R3 gene that cause disrupt gene transcription (Rahrmann et al., 2013). In addition a t(8;11)(q21;q13)PPP6R3/ ATP6V0D2 is found in sarcoma (http://www.tumorfusions.org) and a t(11;17)(q13;q11)PPP6R3/SSH2 is detected in neuroblastoma (McRobert et al., 1992).

Ovarian carcinoma

Ovarian malignancies, a type of gynecological cancer, show high genomic instability and structural chromosomal aberrations which are believed to be common mechanisms for both the inactivation of tumour suppressor genes and the production of fusion genes useful for cancer vitality. The precise roles and functions of these chimeric gene are not always understood (Smebye et al., 2017). The fusion gene DPP9 /PPP6R3 play a role in tumorigenesis and/or cancer progression through the loss-of-function of the DPP9 protein, a serine protease that act as a tumour suppressor and is a inducer of apoptosis.

A fusion gene 5 DPP9 / 3 PPP6R3 deriving from the genomic translocation and fusion of a part of DPP9 (dipeptidyl peptidase 9) gene, situated on chromosome 19 with a portion of PPP6R3 gene, located on chromosome 11 was found in a high-grade serous ovarian carcinoma. The fusion occured between DPP9 exon 11 and PPP6R3 exon 18. DPP9 is a serine protease that act as a tumor suppressor and as a inducer of apoptosis (Smebye et al., 2017).

The fusion between DPP9 and PPP6R3 leads to disruption and deregulation of expression of DPP9 gene due to the introduction of a stop codon (TAG) directly after the junction that leads to the production of truncated form of DPP9 protein. This protein loss some functional domains, i.e. the peptidase and esterase-lipase domains (Smebye et al., 2017) and this causes its loss-of-function.

Pancreatic cancer

The fusion genes PPP6R3/LRP5 and PPP6R3/ SSH3 have been found in pancreas adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)

Testicular germ cell tumors

Testicular germ cell tumors (TGCTs) are the most frequently diagnosed solid malignancies in young males and men by 15 to 44 years old and that includes two main subtypes: seminomas and non-seminomas (Hoff et al., 2016; Znaor et al., 2014). Some authors found a novel fusion gene 5 PPP6R3 - 3 DPP3 in pluripotent embryonal carcinomas (EC) cell lines (Hoff et al., 2016).

The fusion gene 5 PPP6R3 / 3 DPP3 resulting by the translocation t(11;11)(q13;q13) and PPP6R3/DPP3 is a novel genomic chimeric rearrangement occurs in vitro. However more studies are need to characterize it and to elucidate its exact role in testicular germ cell tumors.

PPP6R3-DPP3 fusion gene encodes a protein of 198 amino acids long (Hoff et al., 2016). The functions of this chimeric protein are unknown.

Type 1 diabetes mellitus 4

The IDDM4 locus has been localized to chromosome 11q13 and PPP6R3 gene is linked with type 1 diabetes mellitus 4 (Twells et al., 2001).

Effects on HIV-1 replication

Knockdown of PPP6R3 by short interfering RNAs (siRNA) library screening inhibits HIV-1 replication in cultured Jurkat T-cells (Yeung et al., 2009).