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Park D.J.,University of Melbourne | Tao K.,University of Utah | Le Calvez-Kelm F.,International Agency for Research on Cancer | Nguyen-Dumont T.,University of Melbourne | And 36 more authors.
Cancer Discovery | Year: 2014

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003). © 2014 American Association for Cancer Research.

Ali R.,University of Oxford | Ali R.,United Arab Emirates University | Barnes I.,University of Oxford | Cairns B.J.,University of Oxford | And 5 more authors.
Gut | Year: 2013

Objective: To compare the incidence of six gastrointestinal cancers (colorectal, oesophageal, gastric, liver, gallbladder and pancreatic) among the six main 'non-White' ethnic groups in England (Indian, Pakistani, Bangladeshi, Black African, Black Caribbean and Chinese) to each other and to Whites. Methods: We analysed all 378 511 gastrointestinal cancer registrations from 2001-2007 in England. Ethnicity was obtained by linkage to the Hospital Episodes Statistics database and we used mid-year population estimates from 2001-2007. Incidence rate ratios adjusted for age, sex and income were calculated, comparing the six ethnic groups (and combined 'South Asian' and 'Black' groups) to Whites and to each other. Results: There were significant differences in the incidence of all six cancers between the ethnic groups (all p<0.001). In general, the 'non-White' groups had a lower incidence of colorectal, oesophageal and pancreatic cancer compared to Whites and a higher incidence of liver and gallbladder cancer. Gastric cancer incidence was lower in South Asians but higher in Blacks and Chinese. There was strong evidence of differences in risk between Indians, Pakistanis and Bangladeshis for cancer of the oesophagus, stomach, liver and gallbladder (all p<0.001) and between Black Africans and Black Caribbeans for liver and gallbladder cancer (both p<0.001). Conclusions: The risk of gastrointestinal cancers varies greatly by individual ethnic group, including within those groups that have traditionally been grouped together (South Asians and Blacks). Many of these differences are not readily explained by known risk factors and suggest that important, potentially modifiable causes of these cancers are still to be discovered.

Park D.J.,University of Melbourne | Lesueur F.,International Agency for Research on Cancer | Nguyen-Dumont T.,University of Melbourne | Pertesi M.,International Agency for Research on Cancer | And 27 more authors.
American Journal of Human Genetics | Year: 2012

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases. © 2012 The American Society of Human Genetics.

Deodhar K.K.,Tata Memorial Hospital | Budukh A.,Center for Cancer Epidemiology | Ramadwar M.,Tata Memorial Hospital | Bal M.M.,Tata Memorial Hospital | Shrikhande S.V.,Tata Memorial Hospital
Indian Journal of Pathology and Microbiology | Year: 2012

Introduction: The number of lymph nodes (LNs) retrieved from a specimen of colorectal carcinoma may vary. Factors that can possibly affect LN yield are age of the patient, obesity, location of the tumor, neoadjuvant therapy, surgical technique and pathologist's handling of the specimen. Aim: The aim of our study is to look at lymph node retrieval from colorectal cancer (CRC) specimens in our hands and review the literature. Materials and Methods: From May 2010 to January 2011, a total of 170 colorectal carcinoma cases were operated in our institute. Type of the surgeries, lymph node yield was looked at. Results: There were 103 (60.6%) males and 67 (39.4%) females. The commonest age group was 50-59 years (30.6%). The surgeries included 107 surgeries for rectal carcinoma (63%) and 63 surgeries for colonic carcinoma (37%). Sixty six (38.8%) cases had received preoperative chemoradiotherapy, whereas 104 (61.2%) cases were without adjuvant therapy. The total lymph node positivity (metastatic disease) was 44.7%.The overall mean lymph node yield was 12.68 (range 0-63; median 11). The mean lymph node harvest in the age group < 39 was 15.76 whereas, the lymph node harvest in the group more than 39 years old was 11.90. (statistically significant; P=0.03). The mean lymph node yield from specimens of rectal cancers (10.30) was lower than the mean lymph node yield from specimens for colonic cancers (16.71);(statistically significant, P<0.01). There was also statistically significant difference between the mean LN yield in chemoradionaiive cases (14.63) and in the cases where neoadjuvant therapy was received, (9.59); P<0.01. Conclusion: Pathologist while assessing a specimen of CRC should aim to retrieve a minimum of 12 LN. Surgical expertise and diligence of the pathologists remain two main alterable factors that can improve this yield. Neoadjuvant or preoperative radiotherapy can yield in less number of nodes.

Nagrani R.,Center for Cancer Epidemiology | Mhatre S.,Center for Cancer Epidemiology | Boffetta P.,Mount Sinai School of Medicine | Rajaraman P.,U.S. National Cancer Institute | And 5 more authors.
Cancer Causes and Control | Year: 2016

Purpose: Although cancer registry data indicate that there are large differences in breast cancer (BC) rates between rural and urban regions of India, the reasons for these differences are not well understood. Methods: We conducted a hospital based case–control study (1,637 breast cancer cases; 1,515 visitor controls) in Mumbai, India, during the years 2009–2013. Extensive questionnaire data, anthropometry measurement and blood samples were collected on all participants. Using logistic regression models, we estimated risk based on odds ratio (OR) and 95 % confidence intervals (CI) for various reproductive and anthropometric measures, stratified by rural–urban status depending upon residence in first 20 years of life. Results: Waist-to-hip ratio of ≥0.95 compared to ratio ≤0.84 was strongly associated with risk of BC in both rural and urban populations (ORurban = 4.10, 95 % CI 3.03–5.56; ORrural = 3.01, 95 % CI 1.85–4.90). First full-term pregnancy after the age of 25 compared to first full-term pregnancy below 20 years of age was associated with risk of BC in both urban and rural women (ORurban = 1.78, 95 % CI 1.32–2.41; ORrural = 2.24, 95 % CI 1.13–4.43). The prevalence of age at first full-term pregnancy was significantly lower in rural (mean age at first full-term pregnancy = 19.39 years) versus urban women (mean age at first full-term pregnancy = 22.62 years), whereas mean waist circumference was much higher in urban women (82.13 cm) compared to rural women (79.26 cm). We did not observe any association between breast feeding and risk of BC. Conclusions: Differences in the prevalence of central adiposity and age at first full-term pregnancy between rural and urban women from India may explain some differences in breast cancer rates between these two populations. © 2015, Springer International Publishing Switzerland.

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