Human CDH1 germline mutation encodes for the E-cadherin protein and is responsible for the so-called Hereditary Diffuse Gastric Cancer (HDGC) syndrome (Caldas et al., 1999). Lobular Breast Cancer (LBC) is a component of this inherited disorder as sporadic or familial setting (Corso et al., 2016). Apart from the well-documented association between LBC and HDGC syndrome, novel E-cadherin germline mutations have recently been detected in women affected by LBCs without history for DGC. About 3% of these LBCs carrying CDH1 germline mutations are defined as “hereditary breast tumor” without any manifestation of gastric carcinoma; some studies suspected that this group could be represent an independent cancer syndrome (Benusiglio et al., 2013; Petridis et al., 2014; Corso et al., 2014).
Clinical studies have verified that GC patients with CDH1 germline mutations have shorter survival times (van der Post et al., 2015). Similarly, a worse prognosis is also demonstrated in CDH1 somatic alteration carriers (Corso et al., 2013).
Regarding LBC presenting any CDH1 germline pathogenic alteration, no information is available in the literature about prognosis and overall survival; mutation frequencies are insufficient to perform a complete analysis.
However, patients with hereditary syndrome carrying BRCA1/2 germline mutations have a worse breast cancer-specific survival than to BRCA-negative/sporadic cases (Baretta et al., 2016).
Similar observations are reported in HDGC syndrome, despite the fact that genetic, clinical disease and tumorigenesis are vastly different (van der Post et al., 2015). It seems that patients with hereditary cancer carrying a documented germline mutation show a worse prognosis in comparison to those patients with the wild-type sporadic subset.
In a recent study, Ping et al. (2016) demonstrated that the CDH1 somatic mutation did not impact the prognosis of LBC patients who had an invasive histology; however, the presence of CDH1 plus ERBB2 mutations leads to a worse prognosis. The synergic effect of the CDH1-ERBB2 complex is not well documented; Suriano et al. described EGFR over-expression as being well documented in the presence of CDH1 extracellular domain mutations (Suriano et al., 2003). ERBB2 probably could play a part in this circuit, belonging to the EGFR family.
In this study, ERBB2 mutations were identified in six of the 100 (6%) CDH1-altered LBC and in 6/169 (3.5%) of all screened LBC cases (Ping et al., 2016). It is interesting to observe that germline CDH1 mutations affect about 3% of LBC cases submitted for genetic screening (Corso et al., 2016). There is some clinical and molecular information leading us to suspect that LBC patients described by Ping et al. (2016) could be affected by an inherited syndrome (such as HDGC or sporadic early onset), carrying CDH1 germline mutations. It could be interesting to explore the family history of this sub-group to assess the eligibility of CDH1 genetic screening. Additional further genetic studies will clarify if the presences of CDH1 germline mutation exert a negative prognostic factor in LBC outcome, as hereditary cancer syndrome.
Acknowledgments
We acknowledge Russell Edu Samuel William for the support in editing the draft of this manuscript, and Maria Grazia Villardita for editorial assistance
Footnotes
Conflict of interest
The Authors have no conflict of interests to declare.
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