2013 open access BJC - New perspectives on molecular targeted therapy in ovarian clear cell carcinoma - see Blogger's comments regarding Lynch Syndrome/clear cell ovarian cancer

Blogger's Note: repost/re-review; specific references to clear cell ovarian cancer as it relates to Lynch Syndrome mutations (MLH1; MSH2)

 ~~~~~~~~~~~~~~~~~~~~~

British Journal of Cancer - New perspectives on molecular targeted therapy in ovarian clear cell carcinoma


Loss of mismatch repair genes (hMLH1 and hMSH2;
(Cai et al, 2004; Pal et al, 2008; Ketabi et al, 2011)    7–18% MSI


"Targeting mismatch repair (MMR) defects in OCCCs. Microsatellite
instability (MSI), caused by defects in the DNA MMR
genes, has been observed at high levels (i.e., MSI-high) and low
levels (i.e., MSI-low) in 14% and 7% of OCCCs, respectively, with a
strong correlation between alterations in the expression of hMLH1
and hMSH2 and the presence of MSI in these tumours (Cai et al,
2004). Further evidence that a subset of OCCCs are associated with
MMR defects was observed in a study of Swedish and Danish
Lynch syndrome ovarian cancer patients of which 17% had
OCCCs (Ketabi et al, 2011). A meta-analysis of various histological
subtypes of MMR-deficient EOC has also reported that OCCCs
represent about 18% of these tumours (Pal et al, 2008). The
therapeutic relevance of MMR deficiency has recently been
elucidated in a study demonstrating that methotrexate induces
oxidative DNA damage and is selectively lethal to tumour cells
with MMR defects via inhibition of dihydrofolate reductase (Martin et al, 2009)."


"The distinct molecular features of OCCC and serous ovarian cancer
serve to emphasise the need to develop subtype-specific therapeutic
approaches in the management of EOC. Furthermore, despite
displaying histologically uniform features, OCCCs do not constitute
a single entity and may be classified into distinct molecular
genetic subtypes that also appear to be associated with clinical
outcome (Tan et al, 2011). Additionally, a question which remains
unanswered is whether OCCCs observed in Asian and Western
populations are molecularly distinct entities, which might require
different therapeutic approaches."

Specific references:

• Cai KQ, Albarracin C, Rosen D, Zhong R, Zheng W, Luthra R, Broaddus R, Liu J (2004) Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma. Hum Pathol 35(5): 552–559

• Ketabi Z, Bartuma K, Bernstein I, Malander S, Gronberg H, Bjorck E, Holck S, Nilbert M (2011) Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol 121(3): 462–465.