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Correspondence re: A. Müller et al., Exclusion of Breast Cancer as an Integral Tumor of Hereditary Nonpolyposis Colorectal Cancer. Cancer Res., 62: 1014–1019, 2002.

Department of Pathology, Surgery, and the Foundation for the Detection of Hereditary Tumors, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Letter

In the February 15, 2002 issue of Cancer Research, Müller et al. (1) report on exclusion of breast cancer as an integral tumor of HNPCC.¹ To investigate a proposed association between breast cancer and HNPCC, Müller et al. (1) investigated MSI in a series of 27 female patients who presented with synchronous and metachronous breast tumors plus colorectal tumors. In addition, breast tumors from three female carriers with germ-line mutations in MLH1 or MSH2 were investigated for MSI using the markers D2S123, D5S346, D17S250, BAT25, BAT26, and BAT40. A MSI-high phenotype was found in 5 of 27 (18.5%) of colorectal tumors. Interestingly, no MSI was found in matched breast tumors from patients with a MSI-high phenotype in colorectal tumors. Moreover, breast tumors from female germ-line mutation carriers did not show MSI, whereas colorectal tumors from affected family members exhibit a MSI-high phenotype. Additional immunohistochemical staining for MLH1 and MSH2 proteins revealed no loss of protein staining in any of the breast cancer samples. From these data Müller et al. (1) concluded that most likely breast cancer is not an integral tumor of HNPCC.

We performed MSI analysis in a series of 11 breast tumors from female carriers with germ-line mutations in MLH1, MSH2, or MSH6 of seven unrelated HNPCC families (Table 1) . Using the NCI set of microsatellite markers (D2S123, D5S346, D17S250, BAT25, and BAT26; Ref. 2 ), 7 of 11 (64%) breast tumors exhibit a MSI-high phenotype, and 1 of 11 (9%) tumors exhibit a MSI-low phenotype (instability in BAT26). Additional analyses of mononucleotide repeat markers in candidate target genes (MSH6, MSH3, BRCA1, BRCA2, TGF-ßRII, BAX, and IGF-RII) showed instability in 5 of 11 (45%) breast tumors. In 4 of 11 (38%), instability of the (G)8 repeat in exon 3 of the human BAX gene was found. In one tumor, no instability was found in the NCI set of microsatellite markers, but additional analysis showed instability in the mononucleotide repeat markers of TGF-ßRII, BAX and IGF-RII. In two breast tumors, no MSI was found.

Recently, we evaluated the risk of developing breast cancer in 200 families suspected of HNPCC (6) . We found that breast tumors in these families with HNPCC usually present at early age. However, in contrast to a previous report by Scott et al. (7) , showing an elevated risk of breast cancer, in particularly MLH1 germ-line mutation carriers, we did not find an elevated risk of breast cancer within our series of families. In view of these epidemiological data, we suggest that a defect in the DNA mismatch repair system might be involved in the development of breast cancer but is most likely related to an accelerated tumor progression only at a later stage of tumorigenesis. Whether surveillance of HNPCC patients for the occurrence of breast cancer is indicated needs careful consideration and might be questionable in those families in which breast cancer is not involved.

The detection of an MSI-high phenotype in our series of breast tumors might have three additional implications: (a) breast tumors can be used for MSI testing in families suspected for HNPCC if no other material is available. However, it should be emphasized that the NCI set of microsatellite markers was designed for the screening of MSI in colorectal tumors (8) . It is not completely verified whether this set of markers is applicable and sensitive for MSI analysis in extracolonic tumors such as breast cancer. (b) An MSI-high phenotype might influence the prognosis of breast cancer patients in HNPCC. (c) In colon cancer, there is an ongoing debate whether mismatch repair-deficient tumor cells are sensitive to the standard chemotherapy using 5-fluorouracil compounds. In analogy, a MSI-high phenotype might be important for the choice of adjuvant chemotherapy in the treatment of breast cancer in HNPCC patients. To date, in our series 3 of 11 patients with breast cancer were diagnosed with a positive lymph node status and therefore eligible for chemotherapy.

FOOTNOTES

¹ The abbreviations used are: HNPCC, hereditary nonpolyposis colorectal cancer; MSI, microsatellite instability; NCI, National Cancer Institute; TGF-ßRII, transforming growth factor ß receptor type II; IGF-RII, insulin-like growth factor receptor type II.

Received 4/16/02. Accepted 3/ 1/03.

REFERENCES

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