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4. Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies

Author

Hopper, JL, Li, S, MacInnis, RJ, Dowty, JG, Nguyen, TL, Bui, M, Dite, GS, Esser, VFC, Ye, Z, Makalic, E, Schmidt, DF, Goudey, B, Alpen, K, Kapuscinski, M, Win, AK, Dugue, P-A, Milne, RL, Jayasekara, H, Brooks, JD, Malta, S, Calais-Ferreira, L, Campbell, AC, Young, JT, Nguyen-Dumont, T, Sung, J, Giles, GG, Buchanan, D, Winship, I, Terry, MB, Southey, MC, Jenkins, MA, Hopper, JL, Li, S, MacInnis, RJ, Dowty, JG, Nguyen, TL, Bui, M, Dite, GS, Esser, VFC, Ye, Z, Makalic, E, Schmidt, DF, Goudey, B, Alpen, K, Kapuscinski, M, Win, AK, Dugue, P-A, Milne, RL, Jayasekara, H, Brooks, JD, Malta, S, Calais-Ferreira, L, Campbell, AC, Young, JT, Nguyen-Dumont, T, Sung, J, Giles, GG, Buchanan, D, Winship, I, Terry, MB, Southey, MC, and Jenkins, MA

Abstract

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

Published
2024

6. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Author

Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., Goldberg Y., Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., and Goldberg Y.

Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ackno

Published
2023

13. Diastereoselective oxy-Michael addition of a new chiral water equivalent to electron deficient alkenes : synthesis of 1,2-amino alcohols and b-hydroxy malonates

Author

Buchanan, D. J.

Subjects
547.4
Abstract

Chapters 1 and 2: An introduction to the intermolecular oxy-Michael reaction and a brief overview of the methods used to synthesise 1,2-amino alcohols. Chapter 3: An oxy-Michael reaction was developed whereby the addition of (S)-6-methyltetrahydropyran into a,b-unsaturated monosubstituted nitro compounds allowed rapid access to synthetically important 1,2-amino alcohols. Chapter 4: A logical advancement of the oxy-Michael addition was the addition into a,b-unsaturated disubstituted nitro compounds. These molecules were also converted into the corresponding 1,2-amino alcohols. In addition sequential treatment of the oxy-Michael adduct with TPAP yielded the corresponding b-hydroxy ketone motif. Chapters 5 and 6: The highly stereoselective total syntheses of (R)-pronethalol and (R)-salmeterol were achieved using the new oxy-Michael method as the key step. Chapter 7: An expansion of the methodology to incorporate other conjugate acceptors was considered important. However, analogous d-lactol oxy-Michael additions into crotonate ester and pentenolide were unsuccessful. However, successful oxy-Michael addition into symmetrical a,b-unsaturated malonate systems yielded THP* protected b-hydroxy malonates. It is believed that such motifs shall be capable of transformation into b-hydroxy esters after further development.

Published
2005

16. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, Peters, U, Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, and Peters, U

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Published
2023

17. A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

Author

Walker, R, Mahmood, KE, Joo, J, Clendenning, M, Georgeson, P, Como, J, Joseland, SG, Preston, S, Antill, Y, Austin, R, Boussioutas, A, Bowman, M, Burke, J, Campbell, A, Daneshvar, S, Edwards, E, Gleeson, M, Goodwin, AT, Harris, M, Henderson, A, Higgins, ML, Hopper, JA, Hutchinson, R, Ip, E, Isbister, J, Kasem, K, Marfan, H, Milnes, D, Ng, A, Nichols, C, O'Connell, S, Pachter, NJ, Pope, B, Poplawski, N, Ragunathan, A, Smyth, C, Spigelman, A, Storey, K, Susman, RA, Taylor, J, Warwick, L, Wilding, M, Williams, RK, Win, AD, Walsh, MA, Macrae, FA, Jenkins, M, Rosty, CM, Winship, ID, Buchanan, D, Walker, R, Mahmood, KE, Joo, J, Clendenning, M, Georgeson, P, Como, J, Joseland, SG, Preston, S, Antill, Y, Austin, R, Boussioutas, A, Bowman, M, Burke, J, Campbell, A, Daneshvar, S, Edwards, E, Gleeson, M, Goodwin, AT, Harris, M, Henderson, A, Higgins, ML, Hopper, JA, Hutchinson, R, Ip, E, Isbister, J, Kasem, K, Marfan, H, Milnes, D, Ng, A, Nichols, C, O'Connell, S, Pachter, NJ, Pope, B, Poplawski, N, Ragunathan, A, Smyth, C, Spigelman, A, Storey, K, Susman, RA, Taylor, J, Warwick, L, Wilding, M, Williams, RK, Win, AD, Walsh, MA, Macrae, FA, Jenkins, M, Rosty, CM, Winship, ID, and Buchanan, D

Abstract

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

Published
2023

24. The SCRIPT trial: study protocol for a randomised controlled trial of a polygenic risk score to tailor colorectal cancer screening in primary care

Author

Saya, S, Boyd, L, Chondros, P, McNamara, M, King, M, Milton, S, Lourenco, RDA, Clark, M, Fishman, G, Marker, J, Ostroff, C, Allman, R, Walter, FM, Buchanan, D, Winship, I, McIntosh, J, Macrae, F, Jenkins, M, Emery, J, Saya, S, Boyd, L, Chondros, P, McNamara, M, King, M, Milton, S, Lourenco, RDA, Clark, M, Fishman, G, Marker, J, Ostroff, C, Allman, R, Walter, FM, Buchanan, D, Winship, I, McIntosh, J, Macrae, F, Jenkins, M, and Emery, J

Abstract

BACKGROUND: Polygenic risk scores (PRSs) can predict the risk of colorectal cancer (CRC) and target screening more precisely than current guidelines using age and family history alone. Primary care, as a far-reaching point of healthcare and routine provider of cancer screening and risk information, may be an ideal location for their widespread implementation. METHODS: This trial aims to determine whether the SCRIPT intervention results in more risk-appropriate CRC screening after 12 months in individuals attending general practice, compared with standard cancer risk reduction information. The SCRIPT intervention consists of a CRC PRS, tailored risk-specific screening recommendations and a risk report for participants and their GP, delivered in general practice. Patients aged between 45 and 70 inclusive, attending their GP, will be approached for participation. For those over 50, only those overdue for CRC screening will be eligible to participate. Two hundred and seventy-four participants will be randomised to the intervention or control arms, stratified by general practice, using a computer-generated allocation sequence. The primary outcome is risk-appropriate CRC screening after 12 months. For those in the intervention arm, risk-appropriate screening is defined using PRS-derived risk; for those in the control arm, it is defined using family history and national screening guidelines. Timing, type and results of the previous screening are considered in both arms. Objective health service data will capture screening behaviour. Secondary outcomes include cancer-specific worry, risk perception, predictors of CRC screening behaviour, screening intentions and health service use at 1, 6 and 12 months post-intervention delivery. DISCUSSION: This trial aims to determine whether a PRS-derived personalised CRC risk estimate delivered in primary care increases risk-appropriate CRC screening. A future population risk-stratified CRC screening programme could incorporate risk ass

Published
2022

30. Ian Macalister

Author

Paterson-Brown, P. N. and Buchanan, D. A.

Published
2006

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