Search

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

This study is the first to examine the genetic risk in a breast cancer-prone family wherein two of three triplet sisters and their mother manifested breast cancer. The unaffected triplet, the proband, was found to be monozygotic with her deceased sister through DNA testing of tumor blocks and dizygotic to her living affected sister. Genetic counseling implications are discussed.

Four BRCA2 hereditary breast cancer (HBC) families manifested significant excesses of ‘tubular-lobular group’ (TLG) invasive carcinomas and lobular carcinoma in situ/atypical lobular hyperplasia in comparison to BRCA1-HBC cases.

Patients from hereditary breast cancer-prone (HBC) families provide one of the most powerful and potentially cost effective models for cancer prevention and control. Paradoxically, this opportunity is often missed in the clinical practice setting due, in part, to inattention to the family history and/or lack of knowledge about breast cancer genetics. We describe the family study process, wherein documentation of genealogy, medical, and cancer history through pathology verification is attained, often on extended families. The findings of such studies are illustrated by description of nine breast cancer-prone families. These families illustrate several important clinical/genetic features such as age of cancer onset, bilaterality and/or multiple primary cancer occurrences, incomplete gene penetrance, and the identification of putative obligate gene carriers. Interpretation of HBC pedigrees is dependent upon the understanding of these issues, which in turn may enable the physician to more readily identify those individuals who might benefit from highly targeted breast cancer control measures.

Since full breast cancer screening is not generally recommended for young women, it is important to identify individuals who are at higher risk for early onset breast cancer. We investigated the relationship between age of onset of breast cancer in 328 probands (consecutively ascertained patients from our oncology clinic) and breast cancer incidence and age of onset in their female relatives. We found that a family history of early onset breast cancer was associated with higher risk of early onset breast cancer. A family history of early onset breast cancer occurred more frequently among young (less than 40) breast cancer probands than among older (greater than or equal to 40) breast cancer probands (p less than 0.001; OR = 23). This relationship was particularly evident when the analysis was restricted to the hereditary breast cancer probands (p less than 0.001; OR = 44). We also observed a positive family history of breast cancer (any age) more frequently in young breast cancer probands than in older breast cancer probands (p less than 0.001; OR = 2.8). These observations have important pragmatic implications for surveillance. We recommend intense surveillance for breast cancer, initiated earlier, for women with close relatives diagnosed with early onset breast cancer.

Knowledge of the family history of cancer may significantly influence diagnosis and surgical management. Hereditary breast cancer (HBC) is common and accounts for approximately 9% of the total breast cancer burden. The pattern of HBC's natural history, including age of onset, increased incidence of bilaterality, integral tumor combinations in certain kindreds, and vertical transmission consonant with an autosomal dominantly inherited factor, when observed in context with the family history, enables pattern recognition so that the diagnosis might be facilitated. We describe seven families from our Hereditary Cancer Consultation Center (HCCC) and the Creighton Oncology Clinic which are noteworthy for extraordinarily early age of onset. This appears to be an additional example of heterogeneity in HBC and may represent the first account of this remarkable subset. The manner in which age of onset can be incorporated with other aspects of natural history for expediting diagnosis is discussed.