Jindong Chen

Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma

Hereditary non‐polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, predisposing to the development of colorectal cancer and other tumor types such as endometrial, small bowel, stomach, ovary and urinary tract carcinoma, while most investigators find no association between HNPCC and cancer of the breast. We have identified hMLH1 mutations in 2 Amsterdam‐criteria HNPCC families where both male and female gene carriers were affected with breast cancer. To investigate whether these breast cancers were caused by other genetic factors, we analyzed the 2 breast cancer susceptibility genes BRCA1 and BRCA2. In one family we did not find any mutation in the breast cancer genes, while in the other, a BRCA1 mutation segregated in the breast cancer cases. Hereditary breast cancer, and in particular BRCA1 tumors, display discrete histo‐pathological and immunohistological characteristics. The tumor from a woman with both hMLH1 mutations and a BRCA1 mutation exhibited typical BRCA1 histology, e.g., grade 3 invasive ductal carcinoma with dense lymphocytic infiltration, and immunohistology, estrogen receptor (ER) negative, progesterone receptor (PgR) negative, strongly p53 positive, c‐erbB‐2 negative and highly Ki67 positive (>50% stained cells). The histology of the breast tumor from the man with both one hMLH1 mutation and a BRCA1 mutation was a grade 2 invasive ductal carcinoma without any special BRCA1 features. Immunohistology was also different. This might merely reflect a true difference in male breast tumor progression vs. female. We cannot exclude that the combined effect of BRCA1 and hMLH1 dysfunction has a bearing on tumor progression. Int. J. Cancer 85:796–800, 2000.

Germline mutation screening of the STK11/LKB1 gene in familial breast cancer with LOH on 19p

The recently cloned STK11/LKB1 on chromosome 19p has been shown to be a new tumor suppressor gene. Mutations in the LKB1/STK11 gene on chromosome 19p account for most cases of Peutz–Jeghers syndrome (PJS), in which intestinal hamartomas are associated with elevated risks of several cancer types, including breast cancer. A previous study revealed that familial breast cancer is associated with loss of heterozygosity (LOH) on 19p. To establish whether germline mutations of STK11/LKB1 account for familial breast cancer, 22 patients from 14 breast cancer families with LOH on 19p and one PJS family were selected for screening for germline mutations of LKB1/STK11. A combination of polymerase chain reaction (PCR)‐heteroduplex, single‐strand conformational polymorphism (SSCP) analyses, Southern blot analysis and direct sequencing were used for mutation detection. No mutations were identified. Germline mutations of LKB1/STK11 did not contribute to breast cancer in these families.

BRCA2 germline mutations in Swedish breast cancer families

Mutations in the breast cancer susceptibility gene (BRCA2) are believed to be responsible for a significant fraction of hereditary breast cancer. To determine the BRCA2 mutation spectrum in a subset of Swedish breast cancer families, 162 families were screened for germline mutations in this gene. A combination of RT-PCR, PTT and direct DNA sequencing was used. Two mutations and one previously reported polymorphic variant resulting in a truncated protein were identified. Our data suggest that only a small proportion of Swedish breast cancer families is attributable to BRCA2 germline mutations. This result, in combination with the low frequency of BRCA1 germline mutations identified in our previous study, suggests additional high penetrant as well as low penetrant breast cancer susceptibility genes are involved in familial breast cancer.

Screening for TP53 mutations in patients and tumours from 109 Swedish breast cancer families.

To estimate the prevalence of TP53 mutations in familial breast cancer, constant denaturant gel electrophoresis (CDGE) was used to screen exons 5-8 of the TP53 gene for germline mutations. Genomic DNA from 128 breast cancer patients belonging to 109 families with familial cancer were screened. No germline mutations were found in any of the patients. We also studied TP53 mutations in tumour DNA from 51 of the same individuals and found mutations in 14%. This is similar to what has been reported in sporadic breast cancer.

Screening families with endometrial and colorectal cancers for germline mutations

Editor—Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in the United States and other western countries.1 Although several genes may be altered in these cancers,2 the molecular events in the development of endometrial carcinoma remain poorly defined. Changes in simple sequence repeats in tumour DNA relative to normal DNA, referred to as microsatellite instability (MSI), are a feature of many endometrial carcinomas.3-7 MSI occurs as a result of failing DNA mismatch repair8 and is known to accompany defects in the MLH1 , MSH2 , MSH6 , MSH3 , PMS2 , and possibly PMS1 genes. Apart from MSH3 , all these genes are associated with inherited cancer susceptibility in the context of hereditary non-polyposis colorectal cancer (HNPCC).3 9-16Endometrial carcinomas are the most common extracolonic cancers in HNPCC17 and usually occur at an early age.18Women who carry HNPCC mutations have a 22-43% lifetime risk of developing endometrial cancer as compared with 3% for the general population.19-21 According to a recent report, germline mutations of the DNA mismatch repair gene MSH6 might be specifically associated with susceptibility to endometrial cancer.22 PTEN is a newly isolated tumour suppressor gene located on chromosome 10q23, a region frequently deleted in multiple types of human cancer.23-25 Inactivation of PTEN is the underlying cause of familial Cowden disease.26 Inactivating mutations in the PTEN gene are frequently found in multiple tumour types including brain, breast, prostate, endometrial, and skin carcinomas.23-25 Knockout mice for PTEN die as early embryos, while animals heterozygous for a mutant PTEN allele develop a broad spectrum of tumours.27-29 These observations have established that PTEN has multiple target organs including the endometrium. Recent reports have shown that β-catenin is a multifunctional protein involved in …