Genetic diagnosis of familial breast cancer using clonal sequencing.

Using conventional Sanger sequencing as a reference standard, we compared the sensitivity, specificity, and capacity of the Illumina GA II platform for the detection of TP53, BRCA1, and BRCA2 mutations in established tumor cell lines and DNA from patients with germline mutations. A total of 656 coding variants were identified in four cell lines and 65 patient DNAs. All of the known pathogenic mutations (including point mutations and insertions/deletions of up to 16 nucleotides) were identified, using a combination of the Illumina data analysis pipeline with custom and commercial sequence alignment software. In our configuration, clonal sequencing outperforms current diagnostic methods, providing a reduction in analysis times and in reagent costs compared with conventional sequencing. These improvements open the possibility of BRCA1/2 testing for a wider spectrum of at-risk women, and will allow the genetic classification of tumors prior to the use of novel PARP inhibitors to treat BRCA-deficient breast cancers.

Factors influencing the referrals in primary care of asymptomatic patients with a family history of cancer.

PURPOSE: To describe the events and the reasoning that led UK general practitioners to make a direct referral to a genetics clinic for a family history of cancer. METHODS: Asymptomatic patients with a family history of cancer and general practitioners who had referred them to a genetics clinic were eligible to participate. Semi-structured interviews incorporating a self-completed questionnaire were conducted with the general practitioners. Questions about the referral had to be framed in general terms as few general practitioners could remember the index case. Individual face-to-face interviews based on a topic guide were conducted with the patients. RESULTS: Thirty-six of 54 eligible general practitioners and 71 asymptomatic patients with a family history of cancer completed the study. General practitioners adopted a reactive rather than proactive role in the provision of genetic services for asymptomatic patients with a family history of cancer. Most general practitioners favored cancer diagnostic clinics as a referral pathway, and made a referral to genetics only when patients or a hospital doctor specifically requested this. More idiosyncratic approaches to the referral decision were also encountered. Updating of skills and knowledge in genetics remained a low priority despite acknowledged inadequacies. CONCLUSIONS: Referral guidelines that are practicable in the context of a busy primary care clinic need to be developed if primary care practitioners are to play the major role desired for them in genetics.

Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a young adult male with a novel mutation in the CFTR gene.

Cystic fibrosis is rare in the Asian population, and is often associated with consanguinity and rare genotypes. We report on a 23-year-old Asian man from a consanguineous pedigree referred to the regional cystic fibrosis unit after a diagnosis of congenital bilateral absence of the vas deferens during investigations for infertility. A detailed history revealed several previous episodes of acute pancreatitis. Full diagnostic appraisal showed homozygosity for a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, but normal sweat test and nasal potential difference studies. An endoscopic retrograde cholangiopancreatogram (ERCP) showed chronic pancreatitis with bulky side branches. The vas deferens and the pancreas appeared exquisitely sensitive to mild CFTR dysfunction. Patients with cystic fibrosis and unexplained upper abdominal pain should be screened for pancreatitis, and consideration should be given to screening patients with idiopathic pancreatitis for mutations in the CFTR gene.

Factors influencing consultation to discuss family history of cancer by asymptomatic patients in primary care.

Patient self-initiated consultations to discuss family history of cancer in primary care and the factors leading to these consultations have not been investigated. Seventy-one out of 150 asymptomatic patients with a family history of cancer at the Yorkshire Cancer Genetics Service participated in this study. A semi-structured questionnaire was administered. The results show that (1) family cancer events, doctors' advice and reaching the age of cancer-affected relatives were more salient in raising awareness of the added cancer risk due to family history than media and publicity, and knowledge of the genetics services; (2) knowledge of family medical history and its clinical value is not easy to ascertain; (3) the inter-relationships with other causal beliefs are of interest and could provide insights to understand the factors motivating patients to discuss family history or cancer risk; (4) the belief that 'cancer runs in the family' or is 'a family thing' may not be sufficient to heighten perceived cancer risk and motivate patients to seek medical advice; and (5) understanding of the medical concept and clinical value of family history is poor even in this group of patients who initiated the GP consultations. In conclusion, because most primary care practitioners are likely to rely on patient initiated discussion to identify individuals at an increased risk of cancer because of their family history, these findings are therefore important to help doctors and health providers understand the reasons influencing asymptomatic patients to self-refer themselves in primary care and discuss cancer risk in order to provide appropriate care.

Culture, attitude and knowledge about breast cancer and preventive measures: a qualitative study of South Asian breast cancer patients in the UK.

BACKGROUND: Little is known about the influence of culture and beliefs about breast cancer, and its implications on preventive health behaviour among South Asian people in the UK. METHODS: Using a qualitative approach, 24 South Asian breast cancer patients and their significant others were interviewed. RESULTS: Most patients were unfamiliar with the subject of cancer; they expressed lack of knowledge of cancer as a disease and its symptoms. They identified a painless lump in the breast as sign of abnormality, but not cancer. They also did not know any non-lump breast symptoms. Over half participated in breast screening after encouragement from daughters or relatives. Most did not practise breast self-examination. Perceptions of cancer and health behaviour were influenced by cultural beliefs. Common themes were cancer is a taboo subject and cancer is a stigma. Patients also expressed misunderstandings about the cause of cancer. Cancer in the family had ramifications on children' s marriage prospects and may cause marital breakdown. Terminology used also caused communication problems with healthcare professionals and within the family: the use of ' chest' to substitute ' breast' changed the meaning of the message conveyed. CONCLUSIONS: Cultural beliefs and practices accentuate difficulties in understanding breast cancer, breast screening and breast self-examination, and can prevent South Asian women from adopting preventive health practices.