16q22.1

CDHP,HJMD,PCAD

Various cancers

P-cadherin is altered in various human tumours, but its effective role in the carcinogenesis process remains object of debate, since it can behave differently depending on the studied tumour cell model and context. For example, in melanoma, P-cadherin seems to have a tumour suppressive function, exactly as E-cadherin (Van Marck et al., 2005). In breast cancer P-cadherin is often overexpressed and it is reported to exhibit tumour promoting effects (Paredes et al., 2012). Importantly, P-cadherin upregulation is also found in other malignancies such as gastric, endometrial, colorectal and pancreatic carcinomas (Hardy et al., 2002; Stefansson et al., 2004; Taniuchi et al., 2005; Imai et al., 2008).

Breast cancer

P-cadherin aberrant expression is found in 20% to 40% of invasive breast carcinomas, as well as in 25% of pre-invasive (in situ) ductal carcinomas. Aberrant P-cadherin expression was shown to be associated with tumours of high histological grade, as well as with well established markers of poor prognosis, like Ki-67, EGFR, CK5, vimentin, p53 and HER-2 expression, and negatively associated with age at prognosis and hormonal receptors (ER and PgR) expression. None of these reports showed a significant association with tumour size and lymph node metastasis (Turashvili et al., 2011; Peralta Soler et al., 1999; Gamallo et al., 2001; Paredes et al., 2002; Paredes et al., 2005). P-cadherin aggressive behaviour in breast cancer is dependent on an E-cadherin positive background (Ribeiro et al., 2013) and it is substantially attributed to an increased migratory and invasive capacity of cancer cells (Ribeiro et al., 2010), increased stem cell activity (Vieira et al., 2012) and cross-talk with integrin oncogenic signalling pathways (Vieira et al., 2014).
P-cadherin up-regulation is predominantly found in the basal-like subgroup of breast cancers (Matos et al., 2005; Paredes et al., 2007a; Paredes et al., 2007b) and it is strongly associated with the presence of BRCA1 mutation (Arnes et al., 2005) and poor clinical outcome (Paredes et al., 2005; Turashvili et al., 2011). It has been proposed that P-cadherin in conjugation with vimentin and CK14 constitutes a better criterion for the identification of basal-like breast carcinomas by immunohistochemistry (Sousa et al., 2010).

P-cadherin overexpression in breast cancer is an independent factor of poor prognosis (poor disease free and overall survival) (Paredes et al., 2005; Turashvili et al., 2011).

Hypotrichosis with juvenile macular dystrophy (HJMD)

In humans, the loss of P-cadherin induces characteristic genetic syndromes.
CDH3 gene mutations have been shown to cause P-cadherin functional inactivation, leading to developmental defects associated with hypotrichosis with juvenile macular dystrophy (HJMD) (Sprecher et al., 2001; Avitan-Hersh et al., 2012; Halford et al., 2012).

Hypotrichosis with juvenile macular dystrophy (HJMD; OMIM: 601553) is a rare recessive disorder, characterized by hair loss heralding progressive macular degeneration and early blindness. Affected HJMD individuals are born with seemingly normal hair but develop alopecia of the scalp at around 3 months. After the age of 3 years, affected individuals develop progressive macular degeneration with slight peripheral retinal dystrophy. The severe degenerative changes of the retinal macula culminate in blindness during the second to third decade of life. Since Sprech er et al. (2001) first established a link between this disease and a mutation in gene encoding CDH3/P-cadherin (Sprecher et al., 2001), several other mutations were found, which essentially disturb the Ca2+ binding and the cadherin functional domains or result in the synthesis of a truncated form of P-cadherin or in the absence of P-cadherin expression.

The following allelic variants are responsible for HJMD:
- CDH3, c.2117delG - (Indelman et al., 2003)
- CDH3, IVS12 as A-G -2 - (Shimomura et al., 2010)
- CDH3, IVS10 as G-A -1 - (Jelani et al., 2009; Kamran-ul-Hassan Naqvi et al., 2010)
- CDH3, gDNA 8815bp deleted incl exons 12-13 - (Halford et al., 2012)

Ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM)

CDH3 gene mutations have been shown to cause P-cadherin functional inactivation, leading to ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM syndrome ), a developmental defect associated syndrome. This inherited disease is characterized by sparse hair and macular dystrophy of the retina, and split hand/foot malformation (Kjaer et al., 2005).

This ectodermal defect is characterised by hypotrichosis with sparse and short hair on the scalp, sparse and short eyebrows and eyelashes, and partial anodontia. Different degrees of absence deformities as well as syndactyly have been described, the hands often being more severely affected than the feet. The retinal lesion appears as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels.
Kjaer et al. (2005) first established a link between families with ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM; OMIM: 225280) and homozygous mutations in CDH3/P-cadherin in affected individuals: a missense mutation (114021.0003) and a deletion (114021.0004), respectively (Kjaer et al., 2005).

The following allelic variants are responsible for EEM:
- CDH3, Gly277Val - (Basel-Vanagaite et al., 2010)