The extracolonic cancer spectrum in females with the common ‘South African’ hMLH1 c.C1528T mutation

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, characterized by the occurrence of predominantly colon and endometrial cancer and, less frequently, cancer of the small bowel, stomach, hepatobiliary tract, ureter, renal pelvis, ovaries and brain. The phenotypic diversity may partially be explained by allelic heterogeneity. The aim of this study was to investigate the frequency of extracolonic cancers in a cohort of females sharing the same c.C1528T disease-predisposing mutation in the hMLH1 gene. Data on cancer history were obtained from 87 mutation-positive females and 121 mutation-negative sisters, as a control group. Testing for microsatellite instability (MSI) and expression of the wild-type hMLH1 allele was performed on extra-colonic tumour tissue blocks of mutation-positive individuals. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females vs. 7% (8/121) of mutation-negative females (P = 0.10). Multiple primary cancers occurred at a significantly higher incidence in the first group. Breast cancer, which was the most frequent extra-colonic cancer in mutation positive females (53%), occurred at a young age, and occurred bilaterally in two out of seven cases. Involvement of the hMLH1 gene was confirmed in five out of seven cases of breast cancer, two cases of endometrial cancer, one case of ovarian cancer and one case of renal cell carcinoma, by detecting immunohistochemical compromise of the gene product. Although the study might not have been adequately statistically powered (to provide a significant P value), the noteworthy findings in this study include the confirmation of a range of Lynch II type cancers in a cohort we previously thought was wholly predisposed to Lynch I features, and a confirmation of breast cancer as part of the spectrum of Lynch syndrome cancers affecting women.

Evidence for breast cancer as an integral part of lynch syndrome

“…Breast cancer accounted for 53% of all extracolonic cancers among their female mutation carriers with five of six breast cancer samples exhibiting MSI. From seven cancers assessed for MMR expression, six showed loss of expression (Blokhuis et al, 2008). Finally, a recent study from Shanley et al suggested breast cancer immunohistochemistry as a useful tool in the triage of those Lynch syndrome families where no individual with a ''classic Lynch syndromerelated'' tumor is available for evaluation (Shanley et al, 2009).…”

“…In fact, the lifetime risk for endometrial (Watson et al, 1994;Aarnio et al, 1995;Aarnio et al, 1999) and ovarian cancers (Watson et al, 2001) is estimated at 30-60% and 12%, respectively, compared with 3 and 2%, respectively, in the general population. An elevated risk for breast cancer in Lynch syndrome has been suggested in several studies, but the issue remains controversial (Risinger et al, 1996;Scott et al, 2001;Vasen et al, 2001;Muller et al, 2002;de Leeuw et al, 2003;Oliveira Ferreira et al, 2004;Watson and Riley, 2005;Westenend et al, 2005;Blokhuis et al, 2008;Shanley et al, 2009).…”

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters

“…ECC extracolonic cancer. NEC no extracolonic cancer 1 Data available for 87 mutation positive and 121 mutation negative females 2 Data available for 87 mutation positive and 121 mutation negative females 3 Data available for 80 mutation positive and 98 mutation negative females 4 Data available for 71 mutation positive and 16 mutation negative females 5 Data available for 55 mutation positive and 79 mutation negative females 6 Data available for 32 mutation positive and 42 mutation negative females 7 Data available for 41 mutation positive and 85 mutation negative females 8 Data available for 29 mutation positive and 67 mutation negative females fruit consumption, dietary fibre intake and the use of aspirin were found to be protective factors [6,10]. However, studies on the influence of consumption of alcohol, meat and complex starch found no significant associations with colorectal adenoma formation or cancer risk [5,36,37].…”

“…Prior research in this cohort has investigated the occurrence of extracolonic cancers and the influence of modifier genetic factors on age of cancer onset and cancer diagnosis [3,13]. Notably, breast cancer was the most common extracolonic cancer in the cohort.…”

Alu in Lynch Syndrome: A Danger SINE?

“…Screening for point mutations by exonic sequencing, as well as dosage analysis by multiplex ligation probe amplification (MLPA) to detect structural changes within MLH1 and MSH2 (12), is now routine practice. Founder mutations have been identified in a few ethnic groups, which allow for more cost effective, directed first-pass mutation scanning in relevant populations (2,13,14).…”